Developing vascular networks that integrate with the host circulation and support cells engrafted within engineered tissues remains a key challenge in tissue engineering. Most previous work in this field has focused on developing new methods to build human vascular networks within engineered tissues prior to their implant in vivo, with substantively less attention paid to the role of the host in tissue vascularization and engraftment. Here, we assessed the role that different host animal models and anatomic implant locations play in vascularization and cardiomyocyte survival within engineered tissues. We found major differences in the formation of graft-derived blood vessels and survival of cardiomyocytes after implantation of identical tissues in immunodeficient athymic nude mice
Leucine-rich repeat containing 10 (LRRC10) is a cardiomyocyte-specific protein, but its role in cardiac biology is little understood. Recently Lrrc10 was identified as required for endogenous cardiac regeneration in zebrafish; however, whether LRRC10 plays a role in mammalian heart regeneration remains unclear. In this study, we demonstrate that
- NSF-PAR ID:
- 10435953
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- npj Regenerative Medicine
- Volume:
- 8
- Issue:
- 1
- ISSN:
- 2057-3995
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Myocardial infarction (heart attack) is the number‐one killer of heart patients. Existing treatments do not address cardiomyocyte (CM) loss and cannot regenerate the myocardium. Introducing exogenous cardiac cells is required for heart regeneration due to the lack of resident progenitor cells and very limited proliferative potential of adult CMs. Poor retention of transplanted cells is the critical bottleneck of heart regeneration. Here, the invention of a poly(l‐lactic acid)‐
b ‐poly(ethylene glycol)‐b ‐poly(N‐Isopropylacrylamide) copolymer and its self‐assembly into nanofibrous gelling microspheres (NF‐GMS) is reported. The NF‐GMS undergo a thermally responsive transition to form not only a 3D hydrogel after injection in vivo, but also exhibit characteristics mimicking the native extracellular matrix (ECM) of nanofibrous proteins and gelling proteoglycans or polysaccharides. By integrating the ECM‐mimicking features, injectable form, and the capability of maintaining 3D geometry after injection, the transplantation of hESC‐derived CMs carried by NF‐GMS leads to a striking tenfold graft size increase over direct CM injection in rats, which is the highest reported engraftment to date. Furthermore, NF‐GMS‐carried CM transplantation dramatically reduces infarct size, enhances integration of transplanted CMs, stimulates vascularization in the infarct zone, and leads to a substantial recovery of cardiac function. The NF‐GMS may also be utilized in a variety of biomedical applications. -
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Abstract Background Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due to the more frequent development of subsequent pathological myocardial remodelling and concomitant functional deterioration. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well‐established mouse model of diabetes exposed to MI.
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P < 0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired autophagy in DM + MI mice compared with control mice (P < 0.05). Furthermore, defective autophagy was associated with increased NLRP3 inflammasome and caspase‐1 hyperactivation in DM + MI mouse cardiomyocytes (P < 0.05). Consistent with NLRP3 inflammasome and caspase‐I hyperactivation, cardiomyocyte death and IL‐1β and IL‐18 secretion were increased in DM + MI mice (P < 0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodelling of DM mice after MI.Conclusion In summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagy and associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoring autophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment of post‐infarct remodelling in DM.
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null (Ed.)The present study explores an RNA we have discovered in human heart that induces differentiation of mouse embryonic stem cells and human induced pluripotent stem cells into cardiomyocytes in vitro. We have designated this RNA as Cardiac Inducing RNA or CIR. We now find that CIR also induces mouse embryonic fibroblasts (MEF) to form cardiomyocytes in vitro. For these studies, human-derived CIR is transfected into MEF using lipofectamine. The CIR-transfected mouse fibroblasts exhibit spindle-shaped cells, characteristic of myocardial cells in culture, and express cardiac-specific troponin-T and cardiac tropomyosin. As such, the CIR-induced conversion of the fibroblasts into cardiomyocytes in vitro appears to take place without initial dedifferentiation into pluripotent stem cells. Instead, after CIR transfection using a lipofectamine transfection system, over the next 8 days there appears to be a direct transdifferentiation of ˃80% of the cultured fibroblasts into definitive cardiomyocytes. Fewer than ˂7% of the untreated controls using non-active RNA or lipofectamine by itself show cardiomyocyte characteristics. Thus, discovery of CIR may hold significant potential for future use in repair/regeneration of damaged myocardial tissue in humans after myocardial infarction or other disease processes such that affected patients may be able to return to pre-heart-disease activity levels.more » « less
