Graphene-mediated niches with excellent electroconductibility,good flexibility and convenient modification play a central role in manipulating the cardiogenesis of stem cells.Herein,the graphene derivative matrix of a...Graphene-mediated niches with excellent electroconductibility,good flexibility and convenient modification play a central role in manipulating the cardiogenesis of stem cells.Herein,the graphene derivative matrix of aminated graphene(G-NH_(2))was synthesized as a substrate niche to modulate cardiac differentiation of human induced pluripotent stem cells(hiPSCs).The conductivity of G-NH_(2) matrix was close to that of native myocardium while the surface roughness of G-NH_(2) matrix was much low to present a suitable interface for the adhesion of hiPSCs.The G-NH_(2) matrix effectively elevated the maturation of hiPSCs-derived cardiomyocytes based on the evaluation of cardiomyocyte contraction,sarcomere patterns and length,and the content of NCAD(N-cadherin).The molecular mechanism of cardiomyocyte maturation was highly associated with the signaling pathway of PDGF-β.The mature cardiomyocytes derived from G-NH_(2) were transplanted into the groin of immunodeficient mice to reveal the better survival and rapid angiogenesis.More importantly,in situ injection into rat hearts of differentiated mature cardiomyocytes exhibited the better performance on residence,survival and proliferation.Consequently,we created an instructive stem cell niche of G-NH_(2) matrix that can electrically stimulate various cellular behaviors of hiPSCs in vitro,and the enhanced maturation of hiPSCs-cardiomyocytes manifests favorable activity and function in vivo.展开更多
Cases of inherited retinal dystrophy(IRD)can be caused by mutations in the MERTK gene,which results in an autosomal recessive form of blindness(retinitis pigmentosa,RP)characterized by impaired phagocytosis of photore...Cases of inherited retinal dystrophy(IRD)can be caused by mutations in the MERTK gene,which results in an autosomal recessive form of blindness(retinitis pigmentosa,RP)characterized by impaired phagocytosis of photoreceptor outer segments(Pos)by retinal pigment epithelial cells(RPE).Persistent MERTK gene mutations in patient-derived human induced pluripotent stem cells(hiPSCs)pose a challenge for autologous stem cell-derived RPE replacement therapies targeting IRD.展开更多
Cell therapy has been a promising strategy for cardiac repair after myocardial infarction(MI),but a poor ischemic environment and low cell delivery efficiency remain significant challenges.The spleen serves as a hemat...Cell therapy has been a promising strategy for cardiac repair after myocardial infarction(MI),but a poor ischemic environment and low cell delivery efficiency remain significant challenges.The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI,but it is unclear whether it could be used for human pluripotent stem cell(hiPSC)cultivation and provide a proper microenvironment for cell grafts against the ischemic environment.Herein,we developed a splenic extracellular matrix derived thermoresponsive hydrogel(SpGel).Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway,cell-substrate adhesion,cardiac muscle contraction and oxidation-reduction processes.In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells(iECs)and cardiomyocytes(iCMs)with enhanced function on SpGel.The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven.Furthermore,in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival,revascularization and remuscularization.In conclusion,we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts,which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.展开更多
Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical application...Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.展开更多
基金supported by the National Key Research and Development Program of China(2021YFA1101903,2022YFA1105100)the National Natural Science Foundation of China(32171323,91939111)+2 种基金Science,Technology,and Innovation Commission of Shenzhen Municipality(KCXFZ20211020164544008)DZwas funded by the Ministry of Science and Technology ofChina(National Science and Technology Major Project(2018YFA0109100)the National Natural ScienceFoundation of China(31871496)。
文摘Graphene-mediated niches with excellent electroconductibility,good flexibility and convenient modification play a central role in manipulating the cardiogenesis of stem cells.Herein,the graphene derivative matrix of aminated graphene(G-NH_(2))was synthesized as a substrate niche to modulate cardiac differentiation of human induced pluripotent stem cells(hiPSCs).The conductivity of G-NH_(2) matrix was close to that of native myocardium while the surface roughness of G-NH_(2) matrix was much low to present a suitable interface for the adhesion of hiPSCs.The G-NH_(2) matrix effectively elevated the maturation of hiPSCs-derived cardiomyocytes based on the evaluation of cardiomyocyte contraction,sarcomere patterns and length,and the content of NCAD(N-cadherin).The molecular mechanism of cardiomyocyte maturation was highly associated with the signaling pathway of PDGF-β.The mature cardiomyocytes derived from G-NH_(2) were transplanted into the groin of immunodeficient mice to reveal the better survival and rapid angiogenesis.More importantly,in situ injection into rat hearts of differentiated mature cardiomyocytes exhibited the better performance on residence,survival and proliferation.Consequently,we created an instructive stem cell niche of G-NH_(2) matrix that can electrically stimulate various cellular behaviors of hiPSCs in vitro,and the enhanced maturation of hiPSCs-cardiomyocytes manifests favorable activity and function in vivo.
基金supported by the Norway Grants and Technology Agency of the Czech Republic(KAPPA project No.TO01000107)European Regional Development Fund by Programme Johannes Amos Comenius(No.CZ.02.01.01/00/22_008/0004562 Project"Excellence in Regenerative Medicine")+4 种基金funded by Generalitat Valenciana and co-financed with ERDF funds(OP ERDF of Comunitat Valenciana 2014-2020)supported by funds from Foundation AFM-Telethon(21180)Fundacion Marato TV3 with Ref:202010-10 and CIAICO/2021/115supported by funds from Instituto de Salud Carlos III(ISCIII)of the Spanish Ministry of Health(PI20/01119 to D.L.co-funded by European Regional Development Fund[FEDER funds]"A Way to Make Europe")Univerdidad CEU Cardenal Herrera grant GIR 23/04.
文摘Cases of inherited retinal dystrophy(IRD)can be caused by mutations in the MERTK gene,which results in an autosomal recessive form of blindness(retinitis pigmentosa,RP)characterized by impaired phagocytosis of photoreceptor outer segments(Pos)by retinal pigment epithelial cells(RPE).Persistent MERTK gene mutations in patient-derived human induced pluripotent stem cells(hiPSCs)pose a challenge for autologous stem cell-derived RPE replacement therapies targeting IRD.
基金This work was supported by the Key projects of the National Natural Science Foundation of China(No.81830055)National Science Fund for Distinguished Young Scholars(No.31625011)+1 种基金the National Key Research and Development Program(No.2016YFC1101100)the National Science Fund for Outstanding Young Scholars(No.31822021).
文摘Cell therapy has been a promising strategy for cardiac repair after myocardial infarction(MI),but a poor ischemic environment and low cell delivery efficiency remain significant challenges.The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI,but it is unclear whether it could be used for human pluripotent stem cell(hiPSC)cultivation and provide a proper microenvironment for cell grafts against the ischemic environment.Herein,we developed a splenic extracellular matrix derived thermoresponsive hydrogel(SpGel).Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway,cell-substrate adhesion,cardiac muscle contraction and oxidation-reduction processes.In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells(iECs)and cardiomyocytes(iCMs)with enhanced function on SpGel.The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven.Furthermore,in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival,revascularization and remuscularization.In conclusion,we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts,which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.
基金This work was supported by the National Natural Science Foundation of China[grant numbers 81670270,81970244,81700250].
文摘Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.
