Yusuf Ayesha M, Qaisar Rizwan, Al-Tamimi Abaher O, Jayakumar Manju Nidagodu, Woodgett James R, Koch Walter J, Ahmad Firdos
Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE.
Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
J Cell Physiol. 2022 Mar;237(3):1804-1817. doi: 10.1002/jcp.30644. Epub 2021 Nov 23.
Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here, we sought to identify the potential roles of glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation post-myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension and contractile functions were comparable at 2 weeks post-MI, cKO mice displayed significantly preserved LV chamber and contractile function versus control mice at 4 weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit-positive cells (KPCs) were observed in the cKO hearts at 4 and 6 weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage, as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression and secretion of growth factors, including basic-fibroblast growth factor, angiopoietin-2, erythropoietin, stem cell factor, platelet-derived growth factor-BB, granulocyte colony-stimulating factor, and vascular endothelial growth factor, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte-GSK-3β could be helpful for the promotion of in situ cardiac regeneration post-ischemic injury.
心肌病是一种无法修复的损失，需要新的策略来诱导心脏祖细胞（CPC）原位增殖，以提高心脏再生的可能性。在此，我们试图确定糖原合酶激酶-3β（GSK-3β）这一细胞增殖和分化的关键调节因子在心肌梗死（MI）后CPC增殖中的潜在作用。我们使用了心肌细胞特异性条件性GSK-3β基因敲除（cKO）小鼠和同窝对照小鼠，并对其进行心肌梗死挑战。虽然在心肌梗死后2周，心脏左心室腔大小和收缩功能相当，但与对照小鼠相比，cKO小鼠在心肌梗死后4周时左心室腔和收缩功能得到了显著保留。与保护表型一致，在心肌梗死后4周和6周，cKO心脏中观察到c-kit阳性细胞（KPC）的百分比增加，同时心肌细胞增殖水平也增加。进一步分析表明，缺血性cKO心脏中观察到的KPC数量增加主要来自心脏谱系，因为大多数已鉴定的KPC对造血谱系标记物CD45呈阴性。从机制上讲，心肌细胞中的GSK-3β在缺氧后会深刻抑制包括碱性成纤维细胞生长因子、血管生成素-2、促红细胞生成素、干细胞因子、血小板衍生生长因子-BB、粒细胞集落刺激因子和血管内皮生长因子在内的生长因子的表达和分泌。总之，我们的研究结果强烈表明，心肌细胞中GSK-3β的缺失促进了心肌梗死后心肌细胞和驻留CPC的增殖。缺血性cKO心脏中心肌细胞和CPC增殖的诱导可能受心肌梗死后生长因子失调所控制的自分泌和旁分泌信号调节。抑制心肌细胞GSK-3β的策略可能有助于促进缺血性损伤后的原位心脏再生。
