Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-ter...Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-term results obtained up to now are far from satisfactory.The main causes of these therapeutic limitations are inefficient homing,engraftment,and osteogenic differentiation.Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells.Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation.These strategies could range from a simple modification of the culture conditions,known as cell-preconditioning,to the genetic modification of the cells to avoid cellular senescence.Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation,mainly by the use of bioactive or biomimetic scaffolds,although alternative approaches will also be discussed.This review aims to summarize several of the most recent approaches,providing an up-to-date view of the main developments in MSCbased regenerative techniques.展开更多
BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure...BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure.Bearing this in mind,a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs)to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment.We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English.In PubMed,we initially identified 555 articles and after selection,only 12 were chosen.In Scopus,2010 were identified,and six were left after the screening and eligibility process.RESULTS Of the 2565 articles found in the databases,only 18 original studies met the eligibility criteria.HSC distribution by source showed similar ratios,with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1×10^(7) cells by intravenous or intrabone routes.However,MSCs had a high prevalence of human donors with a variety of sources(umbilical cord blood,bone marrow,tonsil,adipose tissue or fetal lung),using a lower dose,mainly 106 cells and ranging 104 to 1.5×107 cells,utilizing the same routes.MSCs were characterized prior to administration in almost every experiment.The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy.The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism,followed by hematopoietic reconstitution and survival analysis.Besides the engraftment,homing and cellularity were also evaluated in some studies.CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models,in the absence of toxicity.展开更多
Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contribut...Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contributor to cardiac dysfunction after MI,presents as a secondary response to the pathophysiological remodeling of long-standing disease including ischemia,obstruction,and microvascular abnormalities.Cardiac fibroblasts and myofibroblasts are responsible for post-MI remodeling which occurs via regulation of extracellular matrix (ECM),presenting as increased collagenⅠandⅢinto the interstitial and perivascular space.In addition to the pluripotency of stem cells following stem/ progenitor cell transplantation,decreased apoptosis, hypertrophy,and fibrosis in the infarcted heart have been demonstrated.This has made transplantation of progenitor/stem cells a primary research focus in the field of tissue regeneration.Unfortunately,the accumulation of ECM and myofibroblasts in areas of tissue injury presents a barrier that can impair penetration of reparative stem/progenitor cells mobilized from peripheral reservoirs.Therefore,cardiac fibroblast production and degradation of ECM are critical in regulating cardiac remodeling and stem/progenitor cell mobilization.This study used transgenic mice overexpressing adenylyl cyclaseⅥ(AC6) in which collagen synthesis was decreased to determine the role of collagen deposition on the engraftment of iPSC from a tri-cell patch applied to infarcted area after MI.展开更多
Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients...Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization.A total of 294 were enrolled,and 16.0%(n=47)experienced ES after ASCT.The main clinical manifestations were fever(100%),diarrhea(78.7%),skin rash(23.4%),and hypoxemia/pulmonary edema(12.8%).Plerixafor-based mobilization was associated with higher counts of CD3^(+)cells,CD4^(+)cells,and CD8^(+)cells in grafts.In univariate analysis of the total cohort,age≥60 years,receiving ASCT at complete remission(CR),higher number of mononuclear cell(MNC),CD3^(+)cell counts,CD4^(+)cells as well as CD8^(+)cells transfused and plerixafor-based mobilization were associated with ES after ASCT.Multivariate analysis showed that age≥60 years(P=0.0014),receiving ASCT at CR(P=0.002),and higher number of MNC transfused(P=0.026)were associated with ES in total cohort.In plasma cell disease subgroup,age≥60 years(P=0.013),plerixafor-based mobilization(P=0.036),and receiving ASCT at CR(P=0.002)were associated with ES.Patients with more risk factors had a higher risk of ES.The 1-year probabilities of relapse,non-relapse mortality,and survival were comparable between patients with and without ES.Thus,plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES,particularly in patients with plasma cell disease.展开更多
BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secret...BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secretion through paracrine effects but are more susceptible to hypoxic injury post-transplant,while small islets offer better viability and insulin independence.In vivo studies suggest large islets are essential for maintaining euglycemia,though smaller islets are typically preferred in transplantation for better outcomes.AIM To document the impact of islet dimension on clinical and preclinical transplant outcomes to optimize procedures.METHODS PubMed,Scopus and EMBASE platforms were searched for relevant literature up to 9 April 2024.Articles reported on either glucose-stimulated insulin-secreting(GSIS)capacity,islet viability and engraftment,or insulin independence based on the islet dimension were included.The risk of bias was measured using the Appraisal Tool for Cross-Sectional Studies.Extracted data was analyzed via a narrative synthesis.RESULTS Nineteen studies were included in the review.A total of sixteen studies reported the GSIS,of which nine documented the increased insulin secretion in the small islet,where the majority reported insulin secretion per islet equivalent(IEQ).Seven studies documented increased GSIS in large-sized islets that measure insulin secretion per cell or islet.All the articles that compared small and large islets reported poor viability and engraftment of large islets.CONCLUSION Small islets with a diameter<125μm have desired transplantation outcomes due to their better survival following isolation.Large-sized islets receive blood supply directly from arterioles in vivo to meet their higher metabolic demands.The large islet undergoes central necrosis soon after the isolation(devascularization);failing to maintain the viability and glucose stimuli leads to a decline in GSIS and the overall function of the islet.Improved preservation of large islets after islet isolation,enhances the islet yield(IEQ),thereby reducing the likelihood of failed islet isolation and potentially improves transplant outcome.展开更多
BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)wi...BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)with hematological disorders remain unclear.AIM To evaluate the safety and efficacy of rhTPO administered before platelet(PLT)engraftment in pediatric patients with hematological disorders undergoing HSCT,and to investigate its effects on the incidence of graft-vs-host disease(GVHD)and other transplant-related outcomes.METHODS This study enrolled 79 pediatric patients with hematological disorders who received rhTPO after allo-HSCT.The safety and tolerability of rhTPO were evaluated and compared in children(n=36)and adolescents(n=43)with hematological disorders.We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes.Additionally,we examined the efficacy of rhTPO after allo-HSCT in children and adolescents.RESULTS All of the children and adolescents underwent hematopoietic reconstruction.The median time to PLT engraftment was 16 days for all patients,with 14(range,11-24)days in the 0-to 9-year-old group and 16(range,11-41)days in the 10-to 17-year-old group;the difference was statistically significant(P<0.05).The median time to neutrophil engraftment was 12 days in both groups.The median recovery times for PLT counts of≥20×10^(9)/L and≥50×10^(9)/L in the 0-to 9-year-old group were 10(range,2-20)and 11(range,2-20)days,respectively,and those for the 10-to 17-year-old group were 9(range,4-23)and 12(range,5-34)days,respectively.Children exhibited significantly shorter time to PLT engraftment(14 days vs 16 days)and shorter recovery time to PLT count≥100×10^(9)/L(16 days vs 18 days)(P<0.05)than adolescents.The incidence of acute GVHD in all patients was 53.2%,with a higher incidence in children(61.1%)than in adolescents(46.5%).The incidence of chronic GVHD showed little difference between the two age groups,with an overall incidence of 10.1%.No adverse events,other than bleeding,were observed in either age group.The incidence of bleeding was 20.3%.The median follow-up time for all survivors was 573 days(range:42-1803 days)after transplantation.At the final follow-up,3 patients in the 0-to 9-year-old group died;however,none of these deaths were attributed to allo-HSCT or the use of rhTPO.All patients survived in the 10-to 17-year-old group.CONCLUSION rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT.Our results suggested that rhTPO may benefit allo-HSCT in children and adolescents by improving PLT recovery.展开更多
Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require...Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell trans- plantation. It is known that the absence of p18INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow trans- plantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sub- lethally irradiated hosts. We found that p18?/? HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18?/? HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.展开更多
Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding...Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.展开更多
AIM To investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/-total body irradiation(TBI) on outcomes after peripheral blood hematopoietic cell transplant(PBHCT).METH...AIM To investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/-total body irradiation(TBI) on outcomes after peripheral blood hematopoietic cell transplant(PBHCT).METHODS Our retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank test.RESULTS Neutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning(RIC) + TBI] and > 4 × 10~6 CD34+cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group(P = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless ofconditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 ×10~8/kg(3 years, overall survival: 70% vs 38%, P = 0.02, 3 years, progression free survival: 64% vs 38%, P = 0.02).CONCLUSION TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.展开更多
Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (...Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (SCSR-010 Fecal Cell Isolation Kit, NonInvasive Technologies, Elkridge, MD), preserved at room temperature for up to one week, with viability of >85% and low levels of apoptosis (8% - 10%) exhibit two distinct cell size subpopulations, in the 2.5 μM - 5.0 μM and 5.0 μM - 8.0 μM range. In addition to IgA, about 60% of the cells expressed a novel heterodimeric IgA/IgG immunoglobulin that conferred a broad-spectrum cell mediated cytotoxicity against tumor cells. In a cohort of 58 subjects the exclusive absence of this immunoglobulin in two African-Americans was suggestive of a germline deletion. Serial cultures in stem cell medium retained the expression of this heterodimer. Since a majority of the cystic cells expressed the stem cell markers Lgr5 and Musashi-1 we termed these cells as gastrointestinal progenitor stem cells (GIP-C**). CXCR-4, the cytokine co-receptor for HIV was markedly expressed. These cells also expressed CD20, IgA, IgG, CD45, and COX-2. We assume that they originated from mature columnar epithelium by dedifferentiation. Our observations indicate that we have a robust noninvasive method to study mucosal pathophysiology and a direct method to create a database for applications in regenerative medicine.展开更多
When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that ar...When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.展开更多
Objective: To evaluate the significance of two-color interphase fluorescence in situ hybridization (FISH) using X and Y centromere probe in the engraftment estimation and minimal residual disease (MRD) monitoring afte...Objective: To evaluate the significance of two-color interphase fluorescence in situ hybridization (FISH) using X and Y centromere probe in the engraftment estimation and minimal residual disease (MRD) monitoring after allogeneic stem cell transplantation (alloSCT). Methods: Samples from 12 cases patients in different periods after alloSCT were detected by interphase FISH. Results: All of the 12 patients were proved to obtain engraftment 22–35 days after alloSCT. While traditional karyotype showed as 100%XX or 100%XY invariably, FISH showed different percentages of donor original sex chromosome. Conclusion: Two-color interphase FISH is a more sensitive and simple test for engraftment evaluation and MRD monitoring post SCT, though, it can not entirely replace traditional karyotype analysis and gene detection by RT-PCR.展开更多
Objective： Hepatic progenitor cell transplantation has shed light on the treatment of liver failure. The present study was designed to evaluate whether xenogeneic liver epithelial progenitor cells （LEPCs） transplan...Objective： Hepatic progenitor cell transplantation has shed light on the treatment of liver failure. The present study was designed to evaluate whether xenogeneic liver epithelial progenitor cells （LEPCs） transplantation could promote liver recovery in a rat model of acute liver failure. The engraftment and hepatocytic differentiation of transplanted hepatic progenitor cells in the rat spleen was also investigated. Methods： LEPCs were propagated in vitro for long and transduced with lentiviral vector carrying mCherry gene. Intraperitoneal injection of CC14 followed by 2/3 partial hepatectomy three days later were used to establish rat models of acute liver failure. Rats were intrasplenically injected with mCherry modified LEPCs （n=20, 1× 107 cells/0.5 mL） or the same volume of medium （n=20）. Serum liver enzymes （ALT, AST） and liver histology were evaluated for 21 days after transplantation. The engraftment of transplanted LEPCs in the spleens was tested by polymerase chain reaction （PCR） amplification targeting mCherry gene. The differentiation into hepatocytic lineage of transplanted LEPCs was investigated usingimmunohistochemistry staining against Alb. Results： LEPCs were effectively transduced with lentiviral vector showing a transduction efficiency of 90%. Compared with control, cell-injected group displayed significantly lower levels of ALT and AST （P〈0.05） and better histological features including less swelling change and hepatocyte death. PCR amplification of mCherry sequences confirmed the engraftment of LEPCs in the spleens. Alb-positive cells first appeared 5 days after cell transplantation and the number of Alb-positive cells increased substantially （P〈0.05）, which revealed the hepatocytic differentiation process Conclusion： Xenogeneic hepatic progenitor cells can engraft and differentiate into hepatocytes in the splenic parenchyma. Intrasplenic delivery of hepatic progenitor cells ameliorates CCh/partial hepatectomy-induced liver injury in rats展开更多
Primary immunodeficiency disorders (PIDs) result from inborn errors in immunity.Susceptibility to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these disorders.Hematopoieti...Primary immunodeficiency disorders (PIDs) result from inborn errors in immunity.Susceptibility to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these disorders.Hematopoietic cell transplant (HCT) remains the only curative option for many.Severe combined immunodeficiency disorders (SCID) most commonly present at the time of birth and typically require emergent HCT in the first few weeks of life.HCT poses an unusual challenge for PIDs.Donor source and conditioning regimen often impact the outcome of immune reconstitution after HCT in PIDs.The use of matched or unmatched, as well as related versus unrelated donor has resulted in variable outcomes for different subsets of PIDs.Additionally, there is significant variability in the success of engraftment even for a single patient’s lymphocyte subpopulations.While certain cell lines do well without a conditioning regimen, others will not reconstitute unless conditioning is used.The decision to proceed with a conditioning regimen in an already immunocompromised host is further complicated by the fact that alkylating agents should be avoided in radiosensitive PIDs.This manuscript reviews some of the unique elements of HCT in PIDs and evidence-based approaches to transplant in patients with these rare and challenging disorders.展开更多
The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the...The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the potential to differentiate into all kinds of neural cells in vitro.展开更多
Cardiovascular diseases such as myocardial infarction,heart failure,and cardiomyopathy,persist as a leading global cause of death.Current treatment options have inherent limitations,particularly in terms of cardiac re...Cardiovascular diseases such as myocardial infarction,heart failure,and cardiomyopathy,persist as a leading global cause of death.Current treatment options have inherent limitations,particularly in terms of cardiac regeneration due to the limited regenerative capacity of adult human hearts.The transplantation of pluripotent stem cell-derived cardiomyocytes(PSC-CMs)has emerged as a promising and potential solution to address this challenge.This review aims to summarize the latest advancements and prospects of PSC-CM transplantation(PCT),along with the existing constraints,such as immune rejection and engraftment arrhythmias,and corresponding solutions.Encompassing a comprehensive range from fundamental research findings and preclinical experiments to ongoing clinical trials,we hope to offer insights into PCT from bench to bedside.展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enh...The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enhanced platelet engraftment and a favorable safety profile,particularly in younger children aged 0-9 years.This age-dependent difference not only highlights the physiological responsiveness of early hematopoietic environments to rhTPO but also raises important questions about tailoring supportive therapies across pediatric age groups.While the findings are promising,the lack of a control group and single-center limitations warrant further multicenter,long-term investigations.Ne-vertheless,the study lays a compelling foundation for integrating rhTPO more broadly into pediatric transplant protocols and for advancing individualized post-transplant care.展开更多
Background In bone marrow transplant patients, the microenvironment in bone marrow is damaged after chemotherapy or radiotherapy. Subsequent to allogenic hematopoietic stem cell transplantation in patients with clinic...Background In bone marrow transplant patients, the microenvironment in bone marrow is damaged after chemotherapy or radiotherapy. Subsequent to allogenic hematopoietic stem cell transplantation in patients with clinically successful engraftments, the source of mesenchymal stem cells （MSCs） remains controversial. To further verify the stimulatory effect of the simultaneous transplantation of cells from second donors on engraftment success for hematopoietic stem cell transplantation in support of donor MSCs engraftments, the aim of this study is to monitor the dynamics of the engraftment of bone marrow-derived MSCs in patients after transplantation with mismatched-sex hematopoietic stem and third-party cells. Methods In this study, the hematopoietic stem cells from 32 clinical donors of different sexes that resulted in successful engraftments were selected for transplantation and were classified into three groups for research purposes： group A consisted of 14 cases of transplantation with bone marrow and recruited peripheral hematopoietic stem cell transplantation, group B contained 8 cases of simultaneous re-transfusion of MSCs from the second donor, and group C contained 10 cases of simultaneous re-transfusion of umbilical blood from the second donor. The bone marrow from 32 patients with successful engraftments of hematopoietic transplantation were selected and sub-cultured with MSCs. Flow cytometry （FCM） was used to measure the expression of surface antigens on MSCs. Denaturing high-performance liquid chromatography （DHPLC） in combination with polymerase chain reaction amplification of short tandem repeats （STR- PCR） was used to measure the engraftment status of fifth-generation MSCs in patients. Fluorescence in situ hybridization （FISH） revealed the sex origin of the fifth-generation MSCs in 32 patients. Dynamic examinations were performed on patients receiving donor transplantations. Results The progenies of fifth-generation MSCs were successfully cultured in 32 cases. The results of FCM demonstrated that the expression levels of CD14＋ and CD45＋ cells were lower than 0.04% in the fifth-generation MSCs. The analysis using DHPLC and FISH showed similar results. One patient from group B also received a temporary transplantation of MSCs from the donor. The MSCs in the remaining 31 patients all originated from the patients themselves. Conclusions After transplantation, the MSCs present in patients originated from the host. In patients transplanted with MSCs from a second donor, the phenomenon of temporary chimerization of MSCs was observed.展开更多
文摘Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-term results obtained up to now are far from satisfactory.The main causes of these therapeutic limitations are inefficient homing,engraftment,and osteogenic differentiation.Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells.Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation.These strategies could range from a simple modification of the culture conditions,known as cell-preconditioning,to the genetic modification of the cells to avoid cellular senescence.Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation,mainly by the use of bioactive or biomimetic scaffolds,although alternative approaches will also be discussed.This review aims to summarize several of the most recent approaches,providing an up-to-date view of the main developments in MSCbased regenerative techniques.
基金Supported by CNPq,No.308901/2020,No.400856/2016-6FAPESP,No.2019/21070-3,No.2017/17868-4,No.2016/21470-3+2 种基金SisNANO 2.0/MCTIC,No.442539/2019-3the National Institute of Science and Technology Complex Fluids(INCT-FCx)“Amigos da Oncologia e Hematologia Einstein”AMIGOH.
文摘BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure.Bearing this in mind,a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs)to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment.We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English.In PubMed,we initially identified 555 articles and after selection,only 12 were chosen.In Scopus,2010 were identified,and six were left after the screening and eligibility process.RESULTS Of the 2565 articles found in the databases,only 18 original studies met the eligibility criteria.HSC distribution by source showed similar ratios,with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1×10^(7) cells by intravenous or intrabone routes.However,MSCs had a high prevalence of human donors with a variety of sources(umbilical cord blood,bone marrow,tonsil,adipose tissue or fetal lung),using a lower dose,mainly 106 cells and ranging 104 to 1.5×107 cells,utilizing the same routes.MSCs were characterized prior to administration in almost every experiment.The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy.The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism,followed by hematopoietic reconstitution and survival analysis.Besides the engraftment,homing and cellularity were also evaluated in some studies.CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models,in the absence of toxicity.
文摘Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contributor to cardiac dysfunction after MI,presents as a secondary response to the pathophysiological remodeling of long-standing disease including ischemia,obstruction,and microvascular abnormalities.Cardiac fibroblasts and myofibroblasts are responsible for post-MI remodeling which occurs via regulation of extracellular matrix (ECM),presenting as increased collagenⅠandⅢinto the interstitial and perivascular space.In addition to the pluripotency of stem cells following stem/ progenitor cell transplantation,decreased apoptosis, hypertrophy,and fibrosis in the infarcted heart have been demonstrated.This has made transplantation of progenitor/stem cells a primary research focus in the field of tissue regeneration.Unfortunately,the accumulation of ECM and myofibroblasts in areas of tissue injury presents a barrier that can impair penetration of reparative stem/progenitor cells mobilized from peripheral reservoirs.Therefore,cardiac fibroblast production and degradation of ECM are critical in regulating cardiac remodeling and stem/progenitor cell mobilization.This study used transgenic mice overexpressing adenylyl cyclaseⅥ(AC6) in which collagen synthesis was decreased to determine the role of collagen deposition on the engraftment of iPSC from a tri-cell patch applied to infarcted area after MI.
基金supported by the National Key Research and Development Program of China(2022YFC2502606)the National Natural Science Foundation of China(No.82170208,82200239)+3 种基金CAMS Innovation Fund for Medical Sciences(No.2022-I2M-C&T-B-121)Tongzhou district Distinguished Young Scholars(No.JCQN2023009)Peking University Health Science Center-University of Michigan College of Medicine Joint Institute for Translational and Clinical Research(BMU2022JI003)the Fundamental Research Funds for the Central Universities.
文摘Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization.A total of 294 were enrolled,and 16.0%(n=47)experienced ES after ASCT.The main clinical manifestations were fever(100%),diarrhea(78.7%),skin rash(23.4%),and hypoxemia/pulmonary edema(12.8%).Plerixafor-based mobilization was associated with higher counts of CD3^(+)cells,CD4^(+)cells,and CD8^(+)cells in grafts.In univariate analysis of the total cohort,age≥60 years,receiving ASCT at complete remission(CR),higher number of mononuclear cell(MNC),CD3^(+)cell counts,CD4^(+)cells as well as CD8^(+)cells transfused and plerixafor-based mobilization were associated with ES after ASCT.Multivariate analysis showed that age≥60 years(P=0.0014),receiving ASCT at CR(P=0.002),and higher number of MNC transfused(P=0.026)were associated with ES in total cohort.In plasma cell disease subgroup,age≥60 years(P=0.013),plerixafor-based mobilization(P=0.036),and receiving ASCT at CR(P=0.002)were associated with ES.Patients with more risk factors had a higher risk of ES.The 1-year probabilities of relapse,non-relapse mortality,and survival were comparable between patients with and without ES.Thus,plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES,particularly in patients with plasma cell disease.
文摘BACKGROUND Not all islet transplants desirably achieve insulin independence.This can be attributed to the microarchitecture and function of the islets influenced by their dimensions.Large islets enhance insulin secretion through paracrine effects but are more susceptible to hypoxic injury post-transplant,while small islets offer better viability and insulin independence.In vivo studies suggest large islets are essential for maintaining euglycemia,though smaller islets are typically preferred in transplantation for better outcomes.AIM To document the impact of islet dimension on clinical and preclinical transplant outcomes to optimize procedures.METHODS PubMed,Scopus and EMBASE platforms were searched for relevant literature up to 9 April 2024.Articles reported on either glucose-stimulated insulin-secreting(GSIS)capacity,islet viability and engraftment,or insulin independence based on the islet dimension were included.The risk of bias was measured using the Appraisal Tool for Cross-Sectional Studies.Extracted data was analyzed via a narrative synthesis.RESULTS Nineteen studies were included in the review.A total of sixteen studies reported the GSIS,of which nine documented the increased insulin secretion in the small islet,where the majority reported insulin secretion per islet equivalent(IEQ).Seven studies documented increased GSIS in large-sized islets that measure insulin secretion per cell or islet.All the articles that compared small and large islets reported poor viability and engraftment of large islets.CONCLUSION Small islets with a diameter<125μm have desired transplantation outcomes due to their better survival following isolation.Large-sized islets receive blood supply directly from arterioles in vivo to meet their higher metabolic demands.The large islet undergoes central necrosis soon after the isolation(devascularization);failing to maintain the viability and glucose stimuli leads to a decline in GSIS and the overall function of the islet.Improved preservation of large islets after islet isolation,enhances the islet yield(IEQ),thereby reducing the likelihood of failed islet isolation and potentially improves transplant outcome.
文摘BACKGROUND The safety and efficacy of recombinant human thrombopoietin(rhTPO)administered after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in children(0-9 years old)and adolescents(10-17 years old)with hematological disorders remain unclear.AIM To evaluate the safety and efficacy of rhTPO administered before platelet(PLT)engraftment in pediatric patients with hematological disorders undergoing HSCT,and to investigate its effects on the incidence of graft-vs-host disease(GVHD)and other transplant-related outcomes.METHODS This study enrolled 79 pediatric patients with hematological disorders who received rhTPO after allo-HSCT.The safety and tolerability of rhTPO were evaluated and compared in children(n=36)and adolescents(n=43)with hematological disorders.We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes.Additionally,we examined the efficacy of rhTPO after allo-HSCT in children and adolescents.RESULTS All of the children and adolescents underwent hematopoietic reconstruction.The median time to PLT engraftment was 16 days for all patients,with 14(range,11-24)days in the 0-to 9-year-old group and 16(range,11-41)days in the 10-to 17-year-old group;the difference was statistically significant(P<0.05).The median time to neutrophil engraftment was 12 days in both groups.The median recovery times for PLT counts of≥20×10^(9)/L and≥50×10^(9)/L in the 0-to 9-year-old group were 10(range,2-20)and 11(range,2-20)days,respectively,and those for the 10-to 17-year-old group were 9(range,4-23)and 12(range,5-34)days,respectively.Children exhibited significantly shorter time to PLT engraftment(14 days vs 16 days)and shorter recovery time to PLT count≥100×10^(9)/L(16 days vs 18 days)(P<0.05)than adolescents.The incidence of acute GVHD in all patients was 53.2%,with a higher incidence in children(61.1%)than in adolescents(46.5%).The incidence of chronic GVHD showed little difference between the two age groups,with an overall incidence of 10.1%.No adverse events,other than bleeding,were observed in either age group.The incidence of bleeding was 20.3%.The median follow-up time for all survivors was 573 days(range:42-1803 days)after transplantation.At the final follow-up,3 patients in the 0-to 9-year-old group died;however,none of these deaths were attributed to allo-HSCT or the use of rhTPO.All patients survived in the 10-to 17-year-old group.CONCLUSION rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT.Our results suggested that rhTPO may benefit allo-HSCT in children and adolescents by improving PLT recovery.
基金partially supported by the Outstanding Award for Chinese Oversea Scholar by the National Natural Science Foundation of China(Grant No.30228011)the General Award of National Natural Science Foundation of China(Grant No.39970709).
文摘Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell trans- plantation. It is known that the absence of p18INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow trans- plantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sub- lethally irradiated hosts. We found that p18?/? HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18?/? HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.
基金funded by national fundsthrough the Foundation for Science and Technology(FCT)-project UIDB/50026/2020 and UIDP/50026/2020by the National Ataxia Foundation(NAF)
文摘Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.
文摘AIM To investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/-total body irradiation(TBI) on outcomes after peripheral blood hematopoietic cell transplant(PBHCT).METHODS Our retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank test.RESULTS Neutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning(RIC) + TBI] and > 4 × 10~6 CD34+cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group(P = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless ofconditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 ×10~8/kg(3 years, overall survival: 70% vs 38%, P = 0.02, 3 years, progression free survival: 64% vs 38%, P = 0.02).CONCLUSION TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.
文摘Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (SCSR-010 Fecal Cell Isolation Kit, NonInvasive Technologies, Elkridge, MD), preserved at room temperature for up to one week, with viability of >85% and low levels of apoptosis (8% - 10%) exhibit two distinct cell size subpopulations, in the 2.5 μM - 5.0 μM and 5.0 μM - 8.0 μM range. In addition to IgA, about 60% of the cells expressed a novel heterodimeric IgA/IgG immunoglobulin that conferred a broad-spectrum cell mediated cytotoxicity against tumor cells. In a cohort of 58 subjects the exclusive absence of this immunoglobulin in two African-Americans was suggestive of a germline deletion. Serial cultures in stem cell medium retained the expression of this heterodimer. Since a majority of the cystic cells expressed the stem cell markers Lgr5 and Musashi-1 we termed these cells as gastrointestinal progenitor stem cells (GIP-C**). CXCR-4, the cytokine co-receptor for HIV was markedly expressed. These cells also expressed CD20, IgA, IgG, CD45, and COX-2. We assume that they originated from mature columnar epithelium by dedifferentiation. Our observations indicate that we have a robust noninvasive method to study mucosal pathophysiology and a direct method to create a database for applications in regenerative medicine.
基金Supported by a fellowship obt-ained by Nolt-e MA from t-he Landst-einer Foundat-ion for Blood Transfusion Research(www.lsbr.nl),No.#1014
文摘When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.
文摘Objective: To evaluate the significance of two-color interphase fluorescence in situ hybridization (FISH) using X and Y centromere probe in the engraftment estimation and minimal residual disease (MRD) monitoring after allogeneic stem cell transplantation (alloSCT). Methods: Samples from 12 cases patients in different periods after alloSCT were detected by interphase FISH. Results: All of the 12 patients were proved to obtain engraftment 22–35 days after alloSCT. While traditional karyotype showed as 100%XX or 100%XY invariably, FISH showed different percentages of donor original sex chromosome. Conclusion: Two-color interphase FISH is a more sensitive and simple test for engraftment evaluation and MRD monitoring post SCT, though, it can not entirely replace traditional karyotype analysis and gene detection by RT-PCR.
基金Supported by the National Natural Science Foundation of China(30600575,30830099)
文摘Objective： Hepatic progenitor cell transplantation has shed light on the treatment of liver failure. The present study was designed to evaluate whether xenogeneic liver epithelial progenitor cells （LEPCs） transplantation could promote liver recovery in a rat model of acute liver failure. The engraftment and hepatocytic differentiation of transplanted hepatic progenitor cells in the rat spleen was also investigated. Methods： LEPCs were propagated in vitro for long and transduced with lentiviral vector carrying mCherry gene. Intraperitoneal injection of CC14 followed by 2/3 partial hepatectomy three days later were used to establish rat models of acute liver failure. Rats were intrasplenically injected with mCherry modified LEPCs （n=20, 1× 107 cells/0.5 mL） or the same volume of medium （n=20）. Serum liver enzymes （ALT, AST） and liver histology were evaluated for 21 days after transplantation. The engraftment of transplanted LEPCs in the spleens was tested by polymerase chain reaction （PCR） amplification targeting mCherry gene. The differentiation into hepatocytic lineage of transplanted LEPCs was investigated usingimmunohistochemistry staining against Alb. Results： LEPCs were effectively transduced with lentiviral vector showing a transduction efficiency of 90%. Compared with control, cell-injected group displayed significantly lower levels of ALT and AST （P〈0.05） and better histological features including less swelling change and hepatocyte death. PCR amplification of mCherry sequences confirmed the engraftment of LEPCs in the spleens. Alb-positive cells first appeared 5 days after cell transplantation and the number of Alb-positive cells increased substantially （P〈0.05）, which revealed the hepatocytic differentiation process Conclusion： Xenogeneic hepatic progenitor cells can engraft and differentiate into hepatocytes in the splenic parenchyma. Intrasplenic delivery of hepatic progenitor cells ameliorates CCh/partial hepatectomy-induced liver injury in rats
文摘Primary immunodeficiency disorders (PIDs) result from inborn errors in immunity.Susceptibility to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these disorders.Hematopoietic cell transplant (HCT) remains the only curative option for many.Severe combined immunodeficiency disorders (SCID) most commonly present at the time of birth and typically require emergent HCT in the first few weeks of life.HCT poses an unusual challenge for PIDs.Donor source and conditioning regimen often impact the outcome of immune reconstitution after HCT in PIDs.The use of matched or unmatched, as well as related versus unrelated donor has resulted in variable outcomes for different subsets of PIDs.Additionally, there is significant variability in the success of engraftment even for a single patient’s lymphocyte subpopulations.While certain cell lines do well without a conditioning regimen, others will not reconstitute unless conditioning is used.The decision to proceed with a conditioning regimen in an already immunocompromised host is further complicated by the fact that alkylating agents should be avoided in radiosensitive PIDs.This manuscript reviews some of the unique elements of HCT in PIDs and evidence-based approaches to transplant in patients with these rare and challenging disorders.
基金supported by National Program on Key Basic Research Project(973 Programs 2015CB755605)National Natural Science Foundation of China(81471312)
文摘The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the potential to differentiate into all kinds of neural cells in vitro.
基金supported by the Beijing Municipal Science&Technology Commission(Z231100007223001)Beijing Natural Science Foundation(JQ23029,L246020,L244089,L234024,L234021)+9 种基金National Natural Science Foundation of China(82370514,32401144,82472171)Beijing Nova Program(20220484100,20230484448)the Open Research Fund of State Key Laboratory of Cardiovascular Disease,Fuwai Hospital(2022KF-04)Peking Univeristy Medicine Plus X Pilot Program-Platform Construction Project(2024YXXLHPT009)Science Foundation of Peking University Cancer Hospital(JC202508)Scientific and Technological Innovation Project of China Academy of Chinese Medical Science(C12023C056YLL)the Open Research Fund of State Key Laboratory of Digital Medical Engineering,Southeast University(2023K-01)the Open Research Fund from State Key Laboratory of Female Fertility Promotion,Center for Reproductive Medicine,Department of Obstetrics and Gynecology,Peking University Third Hospital(BYSYSZKF2023023)the Innovation and Translation Fund of Peking University Third Hospital(BYSYZHKC2023106)Elite Support Program(jyzc2024-04)。
文摘Cardiovascular diseases such as myocardial infarction,heart failure,and cardiomyopathy,persist as a leading global cause of death.Current treatment options have inherent limitations,particularly in terms of cardiac regeneration due to the limited regenerative capacity of adult human hearts.The transplantation of pluripotent stem cell-derived cardiomyocytes(PSC-CMs)has emerged as a promising and potential solution to address this challenge.This review aims to summarize the latest advancements and prospects of PSC-CM transplantation(PCT),along with the existing constraints,such as immune rejection and engraftment arrhythmias,and corresponding solutions.Encompassing a comprehensive range from fundamental research findings and preclinical experiments to ongoing clinical trials,we hope to offer insights into PCT from bench to bedside.
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
文摘The cohort study by Li et al provides timely and clinically relevant evidence on the use of recombinant human thrombopoietin(rhTPO)in pediatric allogeneic hematopoietic stem cell transplantation.The authors report enhanced platelet engraftment and a favorable safety profile,particularly in younger children aged 0-9 years.This age-dependent difference not only highlights the physiological responsiveness of early hematopoietic environments to rhTPO but also raises important questions about tailoring supportive therapies across pediatric age groups.While the findings are promising,the lack of a control group and single-center limitations warrant further multicenter,long-term investigations.Ne-vertheless,the study lays a compelling foundation for integrating rhTPO more broadly into pediatric transplant protocols and for advancing individualized post-transplant care.
文摘Background In bone marrow transplant patients, the microenvironment in bone marrow is damaged after chemotherapy or radiotherapy. Subsequent to allogenic hematopoietic stem cell transplantation in patients with clinically successful engraftments, the source of mesenchymal stem cells （MSCs） remains controversial. To further verify the stimulatory effect of the simultaneous transplantation of cells from second donors on engraftment success for hematopoietic stem cell transplantation in support of donor MSCs engraftments, the aim of this study is to monitor the dynamics of the engraftment of bone marrow-derived MSCs in patients after transplantation with mismatched-sex hematopoietic stem and third-party cells. Methods In this study, the hematopoietic stem cells from 32 clinical donors of different sexes that resulted in successful engraftments were selected for transplantation and were classified into three groups for research purposes： group A consisted of 14 cases of transplantation with bone marrow and recruited peripheral hematopoietic stem cell transplantation, group B contained 8 cases of simultaneous re-transfusion of MSCs from the second donor, and group C contained 10 cases of simultaneous re-transfusion of umbilical blood from the second donor. The bone marrow from 32 patients with successful engraftments of hematopoietic transplantation were selected and sub-cultured with MSCs. Flow cytometry （FCM） was used to measure the expression of surface antigens on MSCs. Denaturing high-performance liquid chromatography （DHPLC） in combination with polymerase chain reaction amplification of short tandem repeats （STR- PCR） was used to measure the engraftment status of fifth-generation MSCs in patients. Fluorescence in situ hybridization （FISH） revealed the sex origin of the fifth-generation MSCs in 32 patients. Dynamic examinations were performed on patients receiving donor transplantations. Results The progenies of fifth-generation MSCs were successfully cultured in 32 cases. The results of FCM demonstrated that the expression levels of CD14＋ and CD45＋ cells were lower than 0.04% in the fifth-generation MSCs. The analysis using DHPLC and FISH showed similar results. One patient from group B also received a temporary transplantation of MSCs from the donor. The MSCs in the remaining 31 patients all originated from the patients themselves. Conclusions After transplantation, the MSCs present in patients originated from the host. In patients transplanted with MSCs from a second donor, the phenomenon of temporary chimerization of MSCs was observed.
