Abstract
BackgroundParthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; however, their application may be limited without a paternal genome. Insulin-like growth factor-II (IGF-II), a paternally expressed growth hormone, is critical in embryonic differentiation. This study investigated whether forced expression of IGF-II in PSCs can accelerate their differentiation.MethodsOverexpression and re-knockdown of IGF-II in PSCs were performed to investigate the role of IGF-II in PSC differentiation. The derivatives of PSCs with different IGF-II manipulations were transplanted into infarcted murine hearts to investigate the role of IGF-II in cardiomyocyte differentiation in vivo.ResultsData showed that the expression of cardiac troponin T and troponin I in IGF-II-PSC outgrowths preceded that of parental PSC outgrowths, suggesting that IGF-II can accelerate PSC differentiation into cardiac lineage. Overexpression of IGF-II accelerated PSC differentiation towards cardiomyocytes while inhibiting PSC proliferation via the IGF-II/IGF1R signaling. Similar to that observed in cardiac marker expression, on differentiation day 24, IGF-II-PSCs showed PCNA and cyclin D2 expression comparable to juvenile mouse cardiomyocytes, showing that IGF-II-PSCs at this stage possess differential and proliferative properties similar to those of juvenile cardiomyocytes. Moreover, the expression pattern of cardiac markers in IGF-II-overexpressing PSC derivatives resembled that of juvenile mouse cardiomyocytes. After transplantation into the infarcted mouse hearts, IGF-II-PSC-derived cardiomyocytes displayed significant characteristics of mature cardiomyocytes, and IGF-II-depletion by shRNA significantly reversed these effects, suggesting the critical role of IGF-II in promoting cardiomyocyte maturation in vivo. Furthermore, IGF-II-overexpressing PSC derivatives reduced collagen deposition and mitochondrial damage in the infarcted areas and improved cardiac function. The re-knockdown of IGF-II could counteract these favorable effects of IGF-II.ConclusionsThese findings suggest that the ectopic expression of IGF-II accelerates PSC differentiation into the cardiac lineage and promotes cardiomyocyte maturation. The underlying process includes the IGF-II/IGF1R signaling, which is involved in the suppressive effect of IGF-II on PSC proliferation. Moreover, transplanting IGF-II-overexpressing PSC derivatives into the infarcted heart could reduce collagen deposition and improve mitochondria biogenesis and measurements of cardiac function, highlighting the importance of IGF-II in the application of PSCs in cardiac regeneration.
Highlights
Parthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; their application may be limited without a paternal genome
Sui et al Stem Cell Research & Therapy (2020) 11:86 (Continued from previous page). These findings suggest that the ectopic expression of Insulin-like growth factor-II (IGF-II) accelerates PSC differentiation into the cardiac lineage and promotes cardiomyocyte maturation
We presented parthenogenetic stem cells (PSCs) that were haploidentical for major histocompatibility complexes, as an alternative to Human embryonic (ESCs) and induced pluripotent stem cells (iPSCs) in tissue-engineered heart repair with the capacity to differentiate into functional cardiomyocytes [10]
Summary
Parthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; their application may be limited without a paternal genome. Conventional therapies (antiplatelet agents and percutaneous coronary intervention) improve in-hospital mortality, nearly 30% of patients suffer heart failure as a result of continued loss of functional cardiomyocytes [2, 3]. Human embryonic (ESCs) and induced pluripotent stem cells (iPSCs) are sources of cardiomyocytes. Their therapeutic applications are limited by ethical concerns, limited post-transplant cell retention, and immunological rejection to allogeneic cells [8, 9]. We presented parthenogenetic stem cells (PSCs) that were haploidentical for major histocompatibility complexes, as an alternative to ESCs and iPSCs in tissue-engineered heart repair with the capacity to differentiate into functional cardiomyocytes [10]. We generated PSCs that carry cardiac myosin heavy chain-aminoglycoside phosphotransferase (MHC-neor) and enhanced green fluorescence protein (eGFP) to track donor cells during cardiac differentiation and to produce enriched cardiomyocytes by G418 selection [11]
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