Mesenchymal stromal/stem cells(MSCs)have shown significant therapeutic potential,and have therefore been extensively investigated in preclinical studies of regenerative medicine.However,while MSCs have been shown to b...Mesenchymal stromal/stem cells(MSCs)have shown significant therapeutic potential,and have therefore been extensively investigated in preclinical studies of regenerative medicine.However,while MSCs have been shown to be safe as a cellular treatment,they have usually been therapeutically ineffective in human diseases.In fact,in many clinical trials it has been shown that MSCs have moderate or poor efficacy.This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs.Recently,specific priming strategies have been used to improve the therapeutic properties of MSCs.In this review,we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs.We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes.Particularly,while hypoxic priming can be used primarily for the treatment of acute diseases,inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders.The shift in approach from regeneration to inflammation implies,in MSCs,a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways.The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.展开更多
This article presents the stem and progenitor cells from subcutaneous adipose tissue,briefly comparing them with their bone marrow counterparts,and discussing their potential for use in regenerative medicine.Subcutane...This article presents the stem and progenitor cells from subcutaneous adipose tissue,briefly comparing them with their bone marrow counterparts,and discussing their potential for use in regenerative medicine.Subcutaneous adipose tissue differs from other mesenchymal stromal/stem cells(MSCs)sources in that it contains a pre-adipocyte population that dwells in the adventitia of robust blood vessels.Pre-adipocytes are present both in the stromal-vascular fraction(SVF;freshly isolated cells)and in the adherent fraction of adipose stromal/stem cells(ASCs;in vitro expanded cells),and have an active role on the chronic inflammation environment established in obesity,likely due their monocyticmacrophage lineage identity.The SVF and ASCs have been explored in cell therapy protocols with relative success,given their paracrine and immunomodulatory effects.Importantly,the widely explored multipotentiality of ASCs has direct application in bone,cartilage and adipose tissue engineering.The aim of this editorial is to reinforce the peculiarities of the stem and progenitor cells from subcutaneous adipose tissue,revealing the spheroids as a recently described biotechnological tool for cell therapy and tissue engineering.Innovative cell culture techniques,in particular 3D scaffold-free cultures such as spheroids,are now available to increase the potential for regeneration and differentiation of mesenchymal lineages.Spheroids are being explored not only as a model for cell differentiation,but also as powerful 3D cell culture tools to maintain the stemness and expand the regenerative and differentiation capacities of mesenchymal cell lineages.展开更多
Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studie...Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studies have tried to identify the origin of the stromal/stem cell population within adipose tissue in situ. This is a complicated attempt because no marker has currently been described which unambiguously identifies native adipose-derived stromal/stem cells(ASCs). Isolated and cultured ASCs are a non-uniform preparation consisting of several subsets of stem and precursor cells. Cultured ASCs are characterized by their expression of a panel of markers(and the absence of others), whereas their in vitro phenotype is dynamic. Some markers were ex-pressed de novo during culture, the expression of some markers is lost. For a long time, CD34 expression was solely used to characterize haematopoietic stem and progenitor cells, but now it has become evident that it is also a potential marker to identify an ASC subpopula-tion in situ and after a short culture time. Nevertheless, long-term cultured ASCs do not express CD34, perhaps due to the artificial environment. This review gives an update of the recently published data on the origin and phenotype of ASCs both in vivo and in vitro. In addition, the composition of ASCs(or their subpopula-tions) seems to vary between different laboratories andpreparations. This heterogeneity of ASC preparationsmay result from different reasons. One of the main problems in comparing results from different laborato-ries is the lack of a standardized isolation and culture protocol for ASCs. Since many aspects of ASCs, suchas the differential potential or the current use in clinical trials, are fully described in other recent reviews, this review further updates the more basic research issues concerning ASCs' subpopulations, heterogeneity andculture standardization.展开更多
Scaffold-free techniques in the developmental tissue engineering area are designed to mimic in vivo embryonic processes with the aim of biofabricating,in vitro,tissues with more authentic properties.Cell clusters call...Scaffold-free techniques in the developmental tissue engineering area are designed to mimic in vivo embryonic processes with the aim of biofabricating,in vitro,tissues with more authentic properties.Cell clusters called spheroids are the basis for scaffold-free tissue engineering.In this review,we explore the use of spheroids from adult mesenchymal stem/stromal cells as a model in the developmental engineering area in order to mimic the developmental stages of cartilage and bone tissues.Spheroids from adult mesenchymal stromal/stem cells lineages recapitulate crucial events in bone and cartilage formation during embryogenesis,and are capable of spontaneously fusing to other spheroids,making them ideal building blocks for bone and cartilage tissue engineering.Here,we discuss data from ours and other labs on the use of adipose stromal/stem cell spheroids in chondrogenesis and osteogenesis in vitro.Overall,recent studies support the notion that spheroids are ideal"building blocks"for tissue engineering by“bottom-up”approaches,which are based on tissue assembly by advanced techniques such as three-dimensional bioprinting.Further studies on the cellular and molecular mechanisms that orchestrate spheroid fusion are now crucial to support continued development of bottom-up tissue engineering approaches such as three-dimensional bioprinting.展开更多
The increasing prevalence of obesity is alarming because it is a risk factor for cardiovascular and metabolic diseases(such as type 2 diabetes). The occurrence of these comorbidities in obese patients can arise from w...The increasing prevalence of obesity is alarming because it is a risk factor for cardiovascular and metabolic diseases(such as type 2 diabetes). The occurrence of these comorbidities in obese patients can arise from white adipose tissue(WAT) dysfunctions, which affect metabolism, insulin sensitivity and promote local and systemic inflammation. In mammals, WAT depots at different anatomical locations(subcutaneous, preperitoneal and visceral) are highly heterogeneous in their morpho-phenotypic profiles and contribute differently to homeostasis and obesity development, depending on their ability to trigger and modulate WAT inflammation. This heterogeneity is likely due to the differential behavior of cells from each depot. Numerous studies suggest that adiposederived stem/stromal cells(ASC; referred to as adipose progenitor cells, in vivo)with depot-specific gene expression profiles and adipogenic and immunomodulatory potentials are keys for the establishment of the morphofunctional heterogeneity between WAT depots, as well as for the development of depot-specific responses to metabolic challenges. In this review, we discuss depot-specific ASC properties and how they can contribute to the pathophysiology of obesity and metabolic disorders, to provide guidance for researchers and clinicians in the development of ASC-based therapeutic approaches.展开更多
BACKGROUND With recent research advances,adipose-derived stromal/stem cells(ASCs)have been demonstrated to facilitate the survival of fat grafts and thus are increasingly used for reconstructive procedures following s...BACKGROUND With recent research advances,adipose-derived stromal/stem cells(ASCs)have been demonstrated to facilitate the survival of fat grafts and thus are increasingly used for reconstructive procedures following surgery for breast cancer.Unfortunately,in patients,following radiation and chemotherapy for breast cancer suggest that these cancer treatment therapies may limit stem cell cellular functions important for soft tissue wound healing.For clinical translation to patients that have undergone cancer treatment,it is necessary to understand the effects of these therapies on the ASC's ability to improve fat graft survival in clinical practice.AIM To investigate whether the impact on ASCs function capacity and recovery in cancer patients may be due to the chemotherapy.METHODS ASCs were isolated from the cancerous side and noncancerous side of the breast from the same patients with receiving neoadjuvant chemotherapy(NAC)or notreceiving NAC.ASCs were in vitro treated with 5-fluorouracil(5-FU),doxorubicin(DXR),and cyclophosphamide(Cytoxan)at various concentrations.The stem cells yield,cell viability,and proliferation rates were measured by growth curves and MTT assays.Differentiation capacity for adipogenesis was determined by qPCR analysis of the specific gene markers and histological staining.RESULTS No significant differences were observed between the yield of ASCs in patients receiving NAC treatment and not-receiving NAC.ASCs yield from the cancerous side of the breast showed lower than the noncancerous side of the breast in both patients receiving NAC and not-receiving NAC.The proliferation rates of ASCs from patients didn’t differ much before and after NAC upon in vitro culture,and these cells appeared to retain the capacity to acquire adipocyte traits simile to the ASCs from patients not-receiving NAC.After cessation and washout of the drugs for another a week of culturing,ASCs showed a slow recovery of cell growth capacity in 5-FU-treated groups but was not observed in ASCs treated with DXR groups.CONCLUSION Neoadjuvant therapies do not affect the functioning capacity of ASCs.ASCs may hold great potential to serve as a cell source for fat grafting and reconstruction in patients undergoing chemotherapy.展开更多
BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we re...BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims。展开更多
Mesenchymal stromal/stem cells(MSCs)have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential.MSCs play a pivotal role in maintaining tissue homeostasis an...Mesenchymal stromal/stem cells(MSCs)have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential.MSCs play a pivotal role in maintaining tissue homeostasis and possess diverse functions in tissue repair and recovery in various organs.These cells are charac-terized by easy accessibility,few ethical concerns,and adaptability to in vitro cultures,making them a valuable resource for cell therapy in several clinical conditions.Over the years,it has been shown that the true therapeutic power of MSCs lies not in cell engraftment and replacement but in their ability to produce critical paracrine factors,including cytokines,growth factors,and exosomes(EXOs),which modulate the tissue microenvironment and facilitate repair and regeneration processes.Consequently,MSC-derived products,such as condi-tioned media and EXOs,are now being extensively evaluated for their potential medical applications,offering advantages over the long-term use of whole MSCs.However,the efficacy of MSC-based treatments varies in clinical trials due to both intrinsic differences resulting from the choice of diverse cell sources and non-standardized production methods.To address these concerns and to enhance MSC therapeutic potential,researchers have explored many priming strategies,including exposure to inflammatory molecules,hypoxic conditions,and three-dimensional culture techniques.These approaches have optimized MSC secretion of functional factors,empowering them with enhanced immunomodulatory,angiogenic,and regenerative properties tailored to specific medical conditions.In fact,various priming strategies show promise in the treatment of numerous diseases,from immune-related disorders to acute injuries and cancer.Currently,in order to exploit the full therapeutic potential of MSC therapy,the most important challenge is to optimize the modulation of MSCs to obtain adapted cell therapy for specific clinical disorders.In other words,to unlock the complete potential of MSCs in regenerative medicine,it is crucial to identify the most suitable tissue source and develop in vitro manipulation protocols specific to the type of disease being treated.展开更多
This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling.Specifically,it ...This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling.Specifically,it discusses a novel modality of epigenetic regulation,the long noncoding RNAs(lncRNAs),and provides evidence of their involvement in mesenchymal stromal/stem cells osteo-/adipogenic differentiation balance.Despite focus on lncRNAs,there is an emerging cross talk between lncRNAs and miRNAs interaction as a novel mechanism in the regulation of the function of the musculoskeletal system,by controlling bone homeostasis and bone regeneration,as well as the osteogenic differentiation of stem cells.Thus,we touched on some examples to demonstrate this interaction.In addition,we believe there is still much to discover from the effects of lncRNAs on progenitor and non-progenitor cell differentiation.We incorporated data from other published articles to review lncRNAs in normal progenitor cell osteogenic differentiation,determined lncRNAs involved in osteoarthritis pathogenesis in progenitor cells,and provided a review of lncRNAs in non-progenitor cells that are differentially regulated in osteoarthritis.In conclusion,we really enjoyed reading this article and with this information we hope to further our understanding of lncRNAs and mesenchymal stromal/stem cells regulation.展开更多
Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem c...Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering,mesenchymal stem cells(MSCs)are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use.The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs,indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration.Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues,MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years.This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions,giving additional insight into the current clinical application of these cells.展开更多
Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-li...Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-like cells(HLCs)derived from mesenchymal stromal/stem cells(MSCs)offer a promising alternative cell source for hepatocyte therapy,their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy.To this end,MSCs are bioengineered into multicellular spheroids in the present study.The proteomic analyses and experimental results reveal that extracellular vesicles(EVs)derived from these MSC spheroids(SpEV)contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells,resulting in enhanced pro-angiogenic and antioxidative effects.In addition,MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs,particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement.Following orthotopic implantation in the mouse model,the enhanced paracrine effects of SpEV,combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules(ALL),synergically contribute to the effective amelioration of ALF,highlighting the substantial potential for clinical translation.展开更多
Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefi...Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefits for patients.MSCs derived from either human adult or perinatal tissues have their own unique advantages in their medical practices.Usually,clinical studies are conducted by using of cultured MSCs after thawing or short-term cryopreserved-then-thawed MSCs prior to administration for the treatment of a wide range of diseases and medical disorders.Currently,cryogenically banking perinatal MSCs for potential personalized medicine for later use in lifetime has raised growing interest in China as well as in many other countries.Meanwhile,this has led to questions regarding the availability,stability,consistency,multipotency,and therapeutic efficiency of the potential perinatal MSC-derived therapeutic products after longterm cryostorage.This opinion review does not minimize any therapeutic benefit of perinatal MSCs in many diseases after short-term cryopreservation.This article mainly describes what is known about banking perinatal MSCs in China and,importantly,it is to recognize the limitation and uncertainty of the perinatal MSCs stored in cryobanks for stem cell medical treatments in whole life.This article also provides several recommendations for banking of perinatal MSCs for potentially future personalized medicine,albeit it is impossible to anticipate whether the donor will benefit from banked MSCs during her/his lifetime.展开更多
Knee osteoarthritis(KOA),characterized by heterogeneous arthritic manifestations and complex peripheral joint disorder,is one of the leading causes of disability worldwide,which has become a high burden due to the mul...Knee osteoarthritis(KOA),characterized by heterogeneous arthritic manifestations and complex peripheral joint disorder,is one of the leading causes of disability worldwide,which has become a high burden due to the multifactorial nature and the deficiency of available disease-modifying treatments.The application of mesenchymal stem/stromal cells(MSCs)as therapeutic drugs has provided novel treatment options for diverse degenerative and chronic diseases including KOA.However,the complexity and specificity of the“live”cells have posed challenges for MSC-based drug development and the concomitant scale-up preparation from laboratory to industrialization.For instance,despite the considerable progress in ex vivo cell culture technology for fulfilling the robust development of drug conversion and clinical trials,yet significant challenges remain in obtaining regulatory approvals.Thus,there’s an urgent need for the research and development of MSC drugs for KOA.In this review,we provide alternative solution strategies for the preparation of MSC drugs on the basis of the principle of quality by design,including designing the cell production processes,quality control,and clinical applications.In detail,we mainly focus on the quality by design method for MSC manufacturing in standard cell-culturing factories for the treatment of KOA by using the Quality Target Product Profile as a starting point to determine potential critical quality attributes and to establish relationships between critical material attributes and critical process parameters.Collectively,this review aims to meet product performance and robust process design,and should help to reduce the gap between compliant products and the production of compliant good manufacturing practice.展开更多
In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcoh...In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcohol consumption.NAFLD can progress to more serious conditions such as non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.This disease is considered an emerging public health problem in several countries as it has increased in recent decades,currently affecting around 30%of the world’s population.The fatty diet and the current lifestyle of the Western population are identified as the main culprits of the disease.Drug treatment aims to reduce the weight of patients and treat metabolic alterations and diseases,including type 2 diabetes mellitus and other comorbidities that coexist with NAFLD.In this scenario,cell therapy with mesenchymal stem/stromal cells(MSCs)has been proposed as a perspective treatment of numerous diseases that do not have definitive curative treatment,such as Crohn’s disease and coronavirus disease 2019.This is due to the versatile,immunomodulatory and regenerative properties of MSCs.The possibility of MSCs being used in patients with severe liver disease progressing to non-alcoholic steatohepatitis or cirrhosis is summarized,because of the therapeutic benefits in reducing fibrosis of affected livers.It remains to be seen when MSC transplantation should be indicated for NAFLD,that is,at what stage of the disease and which phenotype,as well as deciding on the best source of MSCs,the dose,and the administration route.We conclude that well-designed clinical trials are essential in order to obtain robust results for the implementation of this modality in the medical practice.展开更多
Adipose tissue has emerged as a rich and clinically relevant source of regenerative cells.It offers a minimally invasive,abundant,and autologous reservoir for therapeutic applications.Among its cellular components,the...Adipose tissue has emerged as a rich and clinically relevant source of regenerative cells.It offers a minimally invasive,abundant,and autologous reservoir for therapeutic applications.Among its cellular components,the stromal vascular fraction(SVF)and adipose-derived stem cells(ASCs)have gained considerable attention due to their potent regenerative and immunomodulatory capacities.SVF is a heterogeneous mixture of cells,whereas ASCs constitute a more homogeneous mesenchymal stem cell-like population obtained through in vitro expansion.Together,these cell populations(SVF and ASCs)are described as“living drugs”,as they are viable and act as dynamic biological agents within the body.Unlike conventional medicines,living drugs exert therapeutic effects not only through direct differentiation but also via the secretion of bioactive molecules,including cytokines,growth factors,and extracellular vesicles.These secreted factors can modulate the surrounding microenvironment,enhance tissue repair,and regulate immune responses.Such paracrine mechanisms often play a more significant role than direct cell replacement,making living drugs versatile tools for regenerative medicine.This review provides a comprehensive overview of SVF and ASCs as living drugs.It discusses their cellular composition,mechanisms of action,methods of isolation,and the regenerative biomolecules they secrete.Furthermore,it explores current and emerging clinical applications,challenges,and future innovations.展开更多
文摘Mesenchymal stromal/stem cells(MSCs)have shown significant therapeutic potential,and have therefore been extensively investigated in preclinical studies of regenerative medicine.However,while MSCs have been shown to be safe as a cellular treatment,they have usually been therapeutically ineffective in human diseases.In fact,in many clinical trials it has been shown that MSCs have moderate or poor efficacy.This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs.Recently,specific priming strategies have been used to improve the therapeutic properties of MSCs.In this review,we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs.We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes.Particularly,while hypoxic priming can be used primarily for the treatment of acute diseases,inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders.The shift in approach from regeneration to inflammation implies,in MSCs,a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways.The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
基金Supported by the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro(FAPERJ),No.E-26/202.682/2018
文摘This article presents the stem and progenitor cells from subcutaneous adipose tissue,briefly comparing them with their bone marrow counterparts,and discussing their potential for use in regenerative medicine.Subcutaneous adipose tissue differs from other mesenchymal stromal/stem cells(MSCs)sources in that it contains a pre-adipocyte population that dwells in the adventitia of robust blood vessels.Pre-adipocytes are present both in the stromal-vascular fraction(SVF;freshly isolated cells)and in the adherent fraction of adipose stromal/stem cells(ASCs;in vitro expanded cells),and have an active role on the chronic inflammation environment established in obesity,likely due their monocyticmacrophage lineage identity.The SVF and ASCs have been explored in cell therapy protocols with relative success,given their paracrine and immunomodulatory effects.Importantly,the widely explored multipotentiality of ASCs has direct application in bone,cartilage and adipose tissue engineering.The aim of this editorial is to reinforce the peculiarities of the stem and progenitor cells from subcutaneous adipose tissue,revealing the spheroids as a recently described biotechnological tool for cell therapy and tissue engineering.Innovative cell culture techniques,in particular 3D scaffold-free cultures such as spheroids,are now available to increase the potential for regeneration and differentiation of mesenchymal lineages.Spheroids are being explored not only as a model for cell differentiation,but also as powerful 3D cell culture tools to maintain the stemness and expand the regenerative and differentiation capacities of mesenchymal cell lineages.
文摘Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studies have tried to identify the origin of the stromal/stem cell population within adipose tissue in situ. This is a complicated attempt because no marker has currently been described which unambiguously identifies native adipose-derived stromal/stem cells(ASCs). Isolated and cultured ASCs are a non-uniform preparation consisting of several subsets of stem and precursor cells. Cultured ASCs are characterized by their expression of a panel of markers(and the absence of others), whereas their in vitro phenotype is dynamic. Some markers were ex-pressed de novo during culture, the expression of some markers is lost. For a long time, CD34 expression was solely used to characterize haematopoietic stem and progenitor cells, but now it has become evident that it is also a potential marker to identify an ASC subpopula-tion in situ and after a short culture time. Nevertheless, long-term cultured ASCs do not express CD34, perhaps due to the artificial environment. This review gives an update of the recently published data on the origin and phenotype of ASCs both in vivo and in vitro. In addition, the composition of ASCs(or their subpopula-tions) seems to vary between different laboratories andpreparations. This heterogeneity of ASC preparationsmay result from different reasons. One of the main problems in comparing results from different laborato-ries is the lack of a standardized isolation and culture protocol for ASCs. Since many aspects of ASCs, suchas the differential potential or the current use in clinical trials, are fully described in other recent reviews, this review further updates the more basic research issues concerning ASCs' subpopulations, heterogeneity andculture standardization.
基金the Coordination for the Improvement of Higher Education Personnel(CAPES),No.88882.366181/2019-01the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro(FAPERJ),No.E-26/202.682/2018National Council for Scientific and Technological Development(CNPq),No.467513/2014-7
文摘Scaffold-free techniques in the developmental tissue engineering area are designed to mimic in vivo embryonic processes with the aim of biofabricating,in vitro,tissues with more authentic properties.Cell clusters called spheroids are the basis for scaffold-free tissue engineering.In this review,we explore the use of spheroids from adult mesenchymal stem/stromal cells as a model in the developmental engineering area in order to mimic the developmental stages of cartilage and bone tissues.Spheroids from adult mesenchymal stromal/stem cells lineages recapitulate crucial events in bone and cartilage formation during embryogenesis,and are capable of spontaneously fusing to other spheroids,making them ideal building blocks for bone and cartilage tissue engineering.Here,we discuss data from ours and other labs on the use of adipose stromal/stem cell spheroids in chondrogenesis and osteogenesis in vitro.Overall,recent studies support the notion that spheroids are ideal"building blocks"for tissue engineering by“bottom-up”approaches,which are based on tissue assembly by advanced techniques such as three-dimensional bioprinting.Further studies on the cellular and molecular mechanisms that orchestrate spheroid fusion are now crucial to support continued development of bottom-up tissue engineering approaches such as three-dimensional bioprinting.
基金the National Council for Scientific and Technological Development (CNPq)the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ)the Coordination of High Education Personnel Improvement (CAPES) for financial support
文摘The increasing prevalence of obesity is alarming because it is a risk factor for cardiovascular and metabolic diseases(such as type 2 diabetes). The occurrence of these comorbidities in obese patients can arise from white adipose tissue(WAT) dysfunctions, which affect metabolism, insulin sensitivity and promote local and systemic inflammation. In mammals, WAT depots at different anatomical locations(subcutaneous, preperitoneal and visceral) are highly heterogeneous in their morpho-phenotypic profiles and contribute differently to homeostasis and obesity development, depending on their ability to trigger and modulate WAT inflammation. This heterogeneity is likely due to the differential behavior of cells from each depot. Numerous studies suggest that adiposederived stem/stromal cells(ASC; referred to as adipose progenitor cells, in vivo)with depot-specific gene expression profiles and adipogenic and immunomodulatory potentials are keys for the establishment of the morphofunctional heterogeneity between WAT depots, as well as for the development of depot-specific responses to metabolic challenges. In this review, we discuss depot-specific ASC properties and how they can contribute to the pathophysiology of obesity and metabolic disorders, to provide guidance for researchers and clinicians in the development of ASC-based therapeutic approaches.
文摘BACKGROUND With recent research advances,adipose-derived stromal/stem cells(ASCs)have been demonstrated to facilitate the survival of fat grafts and thus are increasingly used for reconstructive procedures following surgery for breast cancer.Unfortunately,in patients,following radiation and chemotherapy for breast cancer suggest that these cancer treatment therapies may limit stem cell cellular functions important for soft tissue wound healing.For clinical translation to patients that have undergone cancer treatment,it is necessary to understand the effects of these therapies on the ASC's ability to improve fat graft survival in clinical practice.AIM To investigate whether the impact on ASCs function capacity and recovery in cancer patients may be due to the chemotherapy.METHODS ASCs were isolated from the cancerous side and noncancerous side of the breast from the same patients with receiving neoadjuvant chemotherapy(NAC)or notreceiving NAC.ASCs were in vitro treated with 5-fluorouracil(5-FU),doxorubicin(DXR),and cyclophosphamide(Cytoxan)at various concentrations.The stem cells yield,cell viability,and proliferation rates were measured by growth curves and MTT assays.Differentiation capacity for adipogenesis was determined by qPCR analysis of the specific gene markers and histological staining.RESULTS No significant differences were observed between the yield of ASCs in patients receiving NAC treatment and not-receiving NAC.ASCs yield from the cancerous side of the breast showed lower than the noncancerous side of the breast in both patients receiving NAC and not-receiving NAC.The proliferation rates of ASCs from patients didn’t differ much before and after NAC upon in vitro culture,and these cells appeared to retain the capacity to acquire adipocyte traits simile to the ASCs from patients not-receiving NAC.After cessation and washout of the drugs for another a week of culturing,ASCs showed a slow recovery of cell growth capacity in 5-FU-treated groups but was not observed in ASCs treated with DXR groups.CONCLUSION Neoadjuvant therapies do not affect the functioning capacity of ASCs.ASCs may hold great potential to serve as a cell source for fat grafting and reconstruction in patients undergoing chemotherapy.
文摘BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims。
文摘Mesenchymal stromal/stem cells(MSCs)have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential.MSCs play a pivotal role in maintaining tissue homeostasis and possess diverse functions in tissue repair and recovery in various organs.These cells are charac-terized by easy accessibility,few ethical concerns,and adaptability to in vitro cultures,making them a valuable resource for cell therapy in several clinical conditions.Over the years,it has been shown that the true therapeutic power of MSCs lies not in cell engraftment and replacement but in their ability to produce critical paracrine factors,including cytokines,growth factors,and exosomes(EXOs),which modulate the tissue microenvironment and facilitate repair and regeneration processes.Consequently,MSC-derived products,such as condi-tioned media and EXOs,are now being extensively evaluated for their potential medical applications,offering advantages over the long-term use of whole MSCs.However,the efficacy of MSC-based treatments varies in clinical trials due to both intrinsic differences resulting from the choice of diverse cell sources and non-standardized production methods.To address these concerns and to enhance MSC therapeutic potential,researchers have explored many priming strategies,including exposure to inflammatory molecules,hypoxic conditions,and three-dimensional culture techniques.These approaches have optimized MSC secretion of functional factors,empowering them with enhanced immunomodulatory,angiogenic,and regenerative properties tailored to specific medical conditions.In fact,various priming strategies show promise in the treatment of numerous diseases,from immune-related disorders to acute injuries and cancer.Currently,in order to exploit the full therapeutic potential of MSC therapy,the most important challenge is to optimize the modulation of MSCs to obtain adapted cell therapy for specific clinical disorders.In other words,to unlock the complete potential of MSCs in regenerative medicine,it is crucial to identify the most suitable tissue source and develop in vitro manipulation protocols specific to the type of disease being treated.
文摘This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling.Specifically,it discusses a novel modality of epigenetic regulation,the long noncoding RNAs(lncRNAs),and provides evidence of their involvement in mesenchymal stromal/stem cells osteo-/adipogenic differentiation balance.Despite focus on lncRNAs,there is an emerging cross talk between lncRNAs and miRNAs interaction as a novel mechanism in the regulation of the function of the musculoskeletal system,by controlling bone homeostasis and bone regeneration,as well as the osteogenic differentiation of stem cells.Thus,we touched on some examples to demonstrate this interaction.In addition,we believe there is still much to discover from the effects of lncRNAs on progenitor and non-progenitor cell differentiation.We incorporated data from other published articles to review lncRNAs in normal progenitor cell osteogenic differentiation,determined lncRNAs involved in osteoarthritis pathogenesis in progenitor cells,and provided a review of lncRNAs in non-progenitor cells that are differentially regulated in osteoarthritis.In conclusion,we really enjoyed reading this article and with this information we hope to further our understanding of lncRNAs and mesenchymal stromal/stem cells regulation.
基金the Ministry of Education,Science and Technological Development,Republic of Serbia,No.451-03-9/2021-14/200015.
文摘Current research data reveal microenvironment as a significant modifier of physical functions,pathologic changes,as well as the therapeutic effects of stem cells.When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering,mesenchymal stem cells(MSCs)are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use.The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs,indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration.Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues,MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years.This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions,giving additional insight into the current clinical application of these cells.
基金supported by the National Key Research and Devel-opment Program of China(2019YFA0111300)the National Natural Science Foundation of China(52422318,32471423,22277155,52373166)+5 种基金Guangdong Basic and Applied Basic Research Foundation(2022A1515110685,2023A1515011067)the Natural Science Foun-dation of Guangdong Province for Distinguished Young Scholar(2024B1515020025)the Science and Technology Program of Guangz-hou(2025A04J7161,2024A04J6572)the Talent Introduction Program of Postdoctoral International Exchange Program(YJ20200313)the China Primary Health Care Foundation(2022-003)the Thousand Tal-ents Plan,and the Guangdong Provincial Pearl River Talents Program(2019QN01Y131).
文摘Acute liver failure(ALF)is a highly lethal condition characterized by massive tissue necrosis,excessive oxidative stress,and serious inflammatory storms,necessitating prompt medical intervention.Although hepatocyte-like cells(HLCs)derived from mesenchymal stromal/stem cells(MSCs)offer a promising alternative cell source for hepatocyte therapy,their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy.To this end,MSCs are bioengineered into multicellular spheroids in the present study.The proteomic analyses and experimental results reveal that extracellular vesicles(EVs)derived from these MSC spheroids(SpEV)contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells,resulting in enhanced pro-angiogenic and antioxidative effects.In addition,MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs,particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement.Following orthotopic implantation in the mouse model,the enhanced paracrine effects of SpEV,combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules(ALL),synergically contribute to the effective amelioration of ALF,highlighting the substantial potential for clinical translation.
基金Supported by the Henan Province Science and Technique Bureau R&D Project,No.222102310228.
文摘Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefits for patients.MSCs derived from either human adult or perinatal tissues have their own unique advantages in their medical practices.Usually,clinical studies are conducted by using of cultured MSCs after thawing or short-term cryopreserved-then-thawed MSCs prior to administration for the treatment of a wide range of diseases and medical disorders.Currently,cryogenically banking perinatal MSCs for potential personalized medicine for later use in lifetime has raised growing interest in China as well as in many other countries.Meanwhile,this has led to questions regarding the availability,stability,consistency,multipotency,and therapeutic efficiency of the potential perinatal MSC-derived therapeutic products after longterm cryostorage.This opinion review does not minimize any therapeutic benefit of perinatal MSCs in many diseases after short-term cryopreservation.This article mainly describes what is known about banking perinatal MSCs in China and,importantly,it is to recognize the limitation and uncertainty of the perinatal MSCs stored in cryobanks for stem cell medical treatments in whole life.This article also provides several recommendations for banking of perinatal MSCs for potentially future personalized medicine,albeit it is impossible to anticipate whether the donor will benefit from banked MSCs during her/his lifetime.
基金Supported by Taishan Scholar Special Funding,No.tsqnz20240858Medical and Health Technology Project of Shandong Province,No.202402050122+4 种基金Science and Technology Development Plan of Jinan Municipal Health Commission,No.2024301008Clinical Medical Science and Technology Innovation Program of Jinan Science and Technology Bureau,No.202430055Natural Science Foundation of Jiangxi Province,No.20224BAB206077Gansu Provincial Hospital Intra-Hospital Research Fund Project,No.22GSSYB-6and the 2022 Master/Doctor/Postdoctoral Program of National Health Commission Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor,No.NHCDP2022004 and No.NHCDP2022008.
文摘Knee osteoarthritis(KOA),characterized by heterogeneous arthritic manifestations and complex peripheral joint disorder,is one of the leading causes of disability worldwide,which has become a high burden due to the multifactorial nature and the deficiency of available disease-modifying treatments.The application of mesenchymal stem/stromal cells(MSCs)as therapeutic drugs has provided novel treatment options for diverse degenerative and chronic diseases including KOA.However,the complexity and specificity of the“live”cells have posed challenges for MSC-based drug development and the concomitant scale-up preparation from laboratory to industrialization.For instance,despite the considerable progress in ex vivo cell culture technology for fulfilling the robust development of drug conversion and clinical trials,yet significant challenges remain in obtaining regulatory approvals.Thus,there’s an urgent need for the research and development of MSC drugs for KOA.In this review,we provide alternative solution strategies for the preparation of MSC drugs on the basis of the principle of quality by design,including designing the cell production processes,quality control,and clinical applications.In detail,we mainly focus on the quality by design method for MSC manufacturing in standard cell-culturing factories for the treatment of KOA by using the Quality Target Product Profile as a starting point to determine potential critical quality attributes and to establish relationships between critical material attributes and critical process parameters.Collectively,this review aims to meet product performance and robust process design,and should help to reduce the gap between compliant products and the production of compliant good manufacturing practice.
文摘In this editorial,we comment on the article by Jiang et al.Non-alcoholic fatty liver disease(NAFLD)is a chronic liver disease characterized by the accumulation of fat in the liver without evidence of significant alcohol consumption.NAFLD can progress to more serious conditions such as non-alcoholic steatohepatitis,fibrosis,cirrhosis and hepatocellular carcinoma.This disease is considered an emerging public health problem in several countries as it has increased in recent decades,currently affecting around 30%of the world’s population.The fatty diet and the current lifestyle of the Western population are identified as the main culprits of the disease.Drug treatment aims to reduce the weight of patients and treat metabolic alterations and diseases,including type 2 diabetes mellitus and other comorbidities that coexist with NAFLD.In this scenario,cell therapy with mesenchymal stem/stromal cells(MSCs)has been proposed as a perspective treatment of numerous diseases that do not have definitive curative treatment,such as Crohn’s disease and coronavirus disease 2019.This is due to the versatile,immunomodulatory and regenerative properties of MSCs.The possibility of MSCs being used in patients with severe liver disease progressing to non-alcoholic steatohepatitis or cirrhosis is summarized,because of the therapeutic benefits in reducing fibrosis of affected livers.It remains to be seen when MSC transplantation should be indicated for NAFLD,that is,at what stage of the disease and which phenotype,as well as deciding on the best source of MSCs,the dose,and the administration route.We conclude that well-designed clinical trials are essential in order to obtain robust results for the implementation of this modality in the medical practice.
文摘Adipose tissue has emerged as a rich and clinically relevant source of regenerative cells.It offers a minimally invasive,abundant,and autologous reservoir for therapeutic applications.Among its cellular components,the stromal vascular fraction(SVF)and adipose-derived stem cells(ASCs)have gained considerable attention due to their potent regenerative and immunomodulatory capacities.SVF is a heterogeneous mixture of cells,whereas ASCs constitute a more homogeneous mesenchymal stem cell-like population obtained through in vitro expansion.Together,these cell populations(SVF and ASCs)are described as“living drugs”,as they are viable and act as dynamic biological agents within the body.Unlike conventional medicines,living drugs exert therapeutic effects not only through direct differentiation but also via the secretion of bioactive molecules,including cytokines,growth factors,and extracellular vesicles.These secreted factors can modulate the surrounding microenvironment,enhance tissue repair,and regulate immune responses.Such paracrine mechanisms often play a more significant role than direct cell replacement,making living drugs versatile tools for regenerative medicine.This review provides a comprehensive overview of SVF and ASCs as living drugs.It discusses their cellular composition,mechanisms of action,methods of isolation,and the regenerative biomolecules they secrete.Furthermore,it explores current and emerging clinical applications,challenges,and future innovations.
