Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instabili...Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instability. We encourage stem cell scientists to undertake an extensive characterization and standardization of much larger cohorts of iPSC lines in order to set up rigorous criteria to define safe and stable bonafide iPSCs.展开更多
Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are ...Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.展开更多
“Stem Cells is what stem cells does” ... “Stem Cells is what stem cells does” not Forrest Gump In the present day Stem Cells are increasingly becoming popularized as the potential “ultimate” cure for the most challenging maladies… the “Daddy of medical intervention”. Forefront SC research on human induced pluripotent stem cells (iPSCs) and other sub-disciplines, is quickly revolutionizing healthcare towards “Regenerative Medicine”, as beautifully exemplified by the use of iPSCs in treating and possibly curing osteoarthritis, discussed at the end of this publication. This review documents and reflects on the most topical discoveries in SC research, and the challenges researchers in this field nowadays face. Major Findings: 1) In 2006 Yamanaka et al. generated the first iPSCs from mouse fibroblasts, using retroviral transmission of c-Myc, Oct3/4, Klf4 and SOX2 transcription factors. Later, they successfully generated iPSCs from human fibroblasts (2007). 2) Contemporary cultivation methods carry high risks of iPSC genome disruption, possibly leading to tumorigenesis, teratoma formation and reducing iPSC induction efficacy. 3) Many studies on preserving genome integrity and decreasing malignancy in iPSCs, suggest using valiproic acid and protecting tumour suppressor genes. 4) In many malignant tumours only a small minority of cells, called Cancer Stem Cells, metastasise and hyper-proliferate. 5) Not all mature cell sources yield the same [undifferentiated iPSCs: lineage-committed] ratio as others. Feb 2014: Obokata et al. claimed to have generated iPSCs by exposing mature cells to a 25 min, pH 5.7 bath. These iPSCs were termed “Stimulus-triggered Acquisition Pluripotency Cells” (STAP). However by July 2014 this study had been revoked, as the results could not be replicated. Conclusion: Stem cells have enormous potential to offer, especially iPSCs. Although currently not a viable treatment option on their own, for many daunting diseases they will definitely be at the core of multi-disciplined therapies within the near-future, including multi-factorial diseases like osteoarthritis.展开更多
Brugada syndrome(BrS)is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death.Considering that its heterogeneity in clinical manifestations may result from genetic bac...Brugada syndrome(BrS)is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death.Considering that its heterogeneity in clinical manifestations may result from genetic background,the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs)may help to reveal cell phenotype characteristics underlying different genetic variations.Here,to verify and compare the pathogenicity of mutations(SCN5A c.4213G>A and SCN1B c.590C>T)identified from two BrS patients,we generated two novel BrS iPS cell lines that carried missense mutations in SCN5A or SCN1B,compared their structures and electrophysiology,and evaluated the safety of quinidine in patient-specific iPSC-derived CMs.Compared to the control group,BrS-CMs showed a significant reduction in sodium current,prolonged action potential duration,and varying degrees of decreased Vmax,but no structural difference.After applying different concentrations of quinidine,drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration(ETPC).The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A or SCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.展开更多
文摘Here, we provide data suggesting that the absence of silencing of the ectopic reprogramming factors used to reprogram somatic cells to induced pluripotent stem cells （iPSCs） may predispose iPSCs to genomic instability. We encourage stem cell scientists to undertake an extensive characterization and standardization of much larger cohorts of iPSC lines in order to set up rigorous criteria to define safe and stable bonafide iPSCs.
基金supported by the Scientific and Technology Platform and Talents Project of Changsha (No.kh1801129) (to HW)Hunan Cancer Hospital Climb Plan (No.YF2020007) (to HW)+1 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No.LHDMZ22H020001) (To XY)the Science and Technology Program of Jinhua Science and Technology Bureau (No.2021-3-001) (To XY)。
文摘Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.
文摘 “Stem Cells is what stem cells does” not Forrest Gump In the present day Stem Cells are increasingly becoming popularized as the potential “ultimate” cure for the most challenging maladies… the “Daddy of medical intervention”. Forefront SC research on human induced pluripotent stem cells (iPSCs) and other sub-disciplines, is quickly revolutionizing healthcare towards “Regenerative Medicine”, as beautifully exemplified by the use of iPSCs in treating and possibly curing osteoarthritis, discussed at the end of this publication. This review documents and reflects on the most topical discoveries in SC research, and the challenges researchers in this field nowadays face. Major Findings: 1) In 2006 Yamanaka et al. generated the first iPSCs from mouse fibroblasts, using retroviral transmission of c-Myc, Oct3/4, Klf4 and SOX2 transcription factors. Later, they successfully generated iPSCs from human fibroblasts (2007). 2) Contemporary cultivation methods carry high risks of iPSC genome disruption, possibly leading to tumorigenesis, teratoma formation and reducing iPSC induction efficacy. 3) Many studies on preserving genome integrity and decreasing malignancy in iPSCs, suggest using valiproic acid and protecting tumour suppressor genes. 4) In many malignant tumours only a small minority of cells, called Cancer Stem Cells, metastasise and hyper-proliferate. 5) Not all mature cell sources yield the same [undifferentiated iPSCs: lineage-committed] ratio as others. Feb 2014: Obokata et al. claimed to have generated iPSCs by exposing mature cells to a 25 min, pH 5.7 bath. These iPSCs were termed “Stimulus-triggered Acquisition Pluripotency Cells” (STAP). However by July 2014 this study had been revoked, as the results could not be replicated. Conclusion: Stem cells have enormous potential to offer, especially iPSCs. Although currently not a viable treatment option on their own, for many daunting diseases they will definitely be at the core of multi-disciplined therapies within the near-future, including multi-factorial diseases like osteoarthritis.
基金supported by the Natural Science Foundation of Jiangsu Province of China(Grant No.BK20160134 to LW and BK20191071 to CC)National Natural and Science Foundation of China(Grant No.81900295 to CC)Special Foundation for Clinical Science and Technology of Jiangsu Province(Grant No.BE2017754 to HWC).
文摘Brugada syndrome(BrS)is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death.Considering that its heterogeneity in clinical manifestations may result from genetic background,the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs)may help to reveal cell phenotype characteristics underlying different genetic variations.Here,to verify and compare the pathogenicity of mutations(SCN5A c.4213G>A and SCN1B c.590C>T)identified from two BrS patients,we generated two novel BrS iPS cell lines that carried missense mutations in SCN5A or SCN1B,compared their structures and electrophysiology,and evaluated the safety of quinidine in patient-specific iPSC-derived CMs.Compared to the control group,BrS-CMs showed a significant reduction in sodium current,prolonged action potential duration,and varying degrees of decreased Vmax,but no structural difference.After applying different concentrations of quinidine,drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration(ETPC).The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A or SCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.
