12 research outputs found
SWI / SNF in cardiac progenitor cell differentiation
Cardiogenesis requires proper specification, proliferation, and differentiation of cardiac progenitor cells (CPCs). The differentiation of CPCs to specific cardiac cell types is likely guided by a comprehensive network comprised of cardiac transcription factors and epigenetic complexes. In this review, we describe how the ATPâdependent chromatin remodeling SWI/SNF complexes work synergistically with transcription and epigenetic factors to direct specific cardiac gene expression during CPC differentiation. Furthermore, we discuss how SWI/SNF may prime chromatin for cardiac gene expression at a genomeâwide level. A detailed understanding of SWI/SNFâmediated CPC differentiation will provide important insight into the etiology of cardica defects and help design novel therapies for heart disease. J. Cell. Biochem. 114: 2437â2445, 2013. Š 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100161/1/jcb24570.pd
Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts
Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications
Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function
Abstract
Background
Application of cardiac stem cells combined with biomaterial scaffold is a promising therapeutic strategy for heart repair after myocardial infarction. However, the optimal cell types and biomaterials remain elusive.
Methods
In this study, we seeded Isl1+ embryonic cardiac progenitor cells (CPCs) into decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) to assess the therapeutic potential of Isl1+ CPCs and the biocompatibility of SIS-ECM with these cells.
Results
We observed that SIS-ECM supported the viability and attachment of Isl1+ CPCs. Importantly, Isl1+ CPCs differentiated into cardiomyocytes and endothelial cells 7 days after seeding into SIS-ECM. In addition, SIS-ECM with CPC-derived cardiomyocytes showed spontaneous contraction and responded to β-adrenergic stimulation. Next, patches of SIS-ECM seeded with CPCs for 7 days were transplanted onto the outer surface of infarcted myocardium in mice. Four weeks after transplantation, the patches were tightly attached to the surface of the host myocardium and remained viable. Transplantation of patches improved cardiac function, decreased the left ventricular myocardial scarring area, and reduced fibrosis and heart failure.
Conclusions
Transplantation of Isl1+ CPCs seeded in SIS-ECM represents an effective approach for cell-based heart therapy.https://deepblue.lib.umich.edu/bitstream/2027.42/138835/1/13287_2017_Article_675.pd
Murine esBAF chromatin remodeling complex subunits BAF250a and Brg1 are necessary to maintain and reprogram pluripotency-specific replication timing of select replication domains
Background: Cellular differentiation and reprogramming are accompanied by changes in replication timing and 3D organization of large-scale (400 to 800 Kb) chromosomal domains (âreplication domainsâ), but few gene products have been identified whose disruption affects these properties. Results: Here we show that deletion of esBAF chromatin-remodeling complex components BAF250a and Brg1, but not BAF53a, disrupts replication timing at specific replication domains. Also, BAF250a-deficient fibroblasts reprogrammed to a pluripotency-like state failed to reprogram replication timing in many of these same domains. About half of the replication domains affected by Brg1 loss were also affected by BAF250a loss, but a much larger set of domains was affected by BAF250a loss. esBAF binding in the affected replication domains was dependent upon BAF250a but, most affected domains did not contain genes whose transcription was affected by loss of esBAF. Conclusions: Loss of specific esBAF complex subunits alters replication timing of select replication domains in pluripotent cells
Biodegradable Nanofibrous TemperatureâResponsive Gelling Microspheres for Heart Regeneration
Myocardial infarction (heart attack) is the numberâone 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(lâlactic acid)âbâpoly(ethylene glycol)âbâpoly(NâIsopropylacrylamide) copolymer and its selfâassembly into nanofibrous gelling microspheres (NFâGMS) is reported. The NFâGMS 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 ECMâmimicking features, injectable form, and the capability of maintaining 3D geometry after injection, the transplantation of hESCâderived CMs carried by NFâGMS leads to a striking tenfold graft size increase over direct CM injection in rats, which is the highest reported engraftment to date. Furthermore, NFâGMSâcarried 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 NFâGMS may also be utilized in a variety of biomedical applications.A triâblock copolymer is synthesized that selfâassembles into porous nanofibrous microspheres. These microspheres in an aqueous suspension form a hydrogel upon temperature increase to body temperature. These nanofibrous gelling microspheres are used to deliver cardiomyocytes into an infarcted rat heart and result in the highest cardiomyocyte engraftment to date, dramatically reduce infarct size, and lead to a substantial cardiac functional recovery.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155499/1/adfm202000776-sup-0001-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155499/2/adfm202000776_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155499/3/adfm202000776.pd
BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation
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Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice.
Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice. We demonstrate that ARID1A is essential for maintaining the frequency and function of hematopoietic stem cells and its loss impairs the differentiation of both myeloid and lymphoid lineages. ARID1A deficiency led to a global reduction in open chromatin and ensuing transcriptional changes affected key genes involved in hematopoietic development. We also observed that silencing of ARID1A affected ATRA-induced differentiation of NB4 cells, suggesting its role in granulocytic differentiation of human leukemic cells. Overall, our study provides a comprehensive elucidation of the function of ARID1A in hematopoiesis and highlights the central role of ARID1A-containing SWI/SNF complex in maintaining chromatin dynamics in hematopoietic cells
Additional file 1: Figure S1. of Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function
Showing the proliferation rate of Isl1+ cells by staining with mitotic marker ki67. (TIF 862 kb
Additional file 2: Figure S2. of Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function
Showing detection of Isl1+ CPC-derived cell viability in SIS-ECM patches 28 days after transplantation. Frozen sections of mouse hearts subjected to myocardial infarction and transplantation of SIS-ECM-CPC patches before (AâÂÂC) and after fixation by 4% paraformaldehyde (D) obtained by bright-field (A) and fluorescence microscopy (BâÂÂD). (TIF 6084 kb
HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarctionResearch in context
Background: Epigenetic histone acetylation is a major event controlling cell functions, such as metabolism, differentiation and repair. Here, we aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways. Methods: VPA was administrated to MI rats at different time points, onset and after MI injury. Echocardiography, histology, serum biology assays, and gene expression, inhibition, and over-expression were performed to characterize the systolic function, infarct size, gene and signaling pathways. Findings: VPA treatment reduced the infarct size by ~50% and preserved the systolic function of heart after acute MI in rats. Even 60âŻmin after infarction, VPA treatment significantly decreased infarct size. Furthermore, long-term treatment of VPA markedly improved myocardial performance. VPA regulated gene expression essential for cell survival and anti-inflammatory response. Consequently, oxidative stress and cell death were notably reduced after VPA treatment. Moreover, Foxm1 was identified as a potential key target of VPA. Overexpression of Foxm1 provided similar heart protective effect to VPA treatment. Particularly, both VPA treatment and Foxm1 over-expression repressed inflammatory response after MI for heart protection. In contrast, inhibition of Foxm1 activity abolished the cardiac protective effect of VPA. VPA mediated CM protection through Foxm1 upregulation was also identified in a human ESC derived CM hypoxia/reperfusion system. Interpretation: VPA treatments significantly reduce cardiac damage after MI and the cardioprotective effect of VPA is likely mediated via Foxm1 pathway. Fund: This work was mainly supported by 1R01HL109054. Keywords: Valproic acid, Myocardial infarction, Foxm1, Cardiomyocyte protectio