Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism

Abstract

Background The human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms. Methods Comparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts. Results In vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group. Conclusion hEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.

Cardiomyocyte‐GSK‐3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

“…Angpt2 plays an important role in vascular angiogenesis and enhances endothelial cell survival through stimulating PI3K‐Akt signaling (Kim et al, 2000). It is also evident that human endometrium‐derived stem cells transplantation facilitates post‐MI cardiac repair due to an upregulation of proangiogenic molecules, including angpt2 (Fan et al, 2021). The role of angpt2 in cell proliferation or differentiation is unknown.…”

Muscle and Adipose Tissue Communicate with Extracellular Vesicles

“…Inside adipose tissue, adipose-derived mesenchymal stem cells have emerged as important actors for cardio-protection because of their capacities to stimulate angiogenesis and to inhibit apoptosis [35]. Indeed, AT-derived stem cells can be easily isolated and have a strong capacity to proliferate and to differentiate into both cardiomyocytes and endothelial cells.…”

Uterus: A Unique Stem Cell Reservoir Able to Support Cardiac Repair via Crosstalk among Uterus, Heart, and Bone Marrow

“…In response to an ischemic injury to the heart, the recruitment of regenerative cells has been demonstrated to be essential for recovery [ 71 , 77 , 78 , 79 , 80 , 81 ]. According to our research findings, females may have the advantage, owing to the proposed utero-cardiac axis, which provides additional support for cardiac healing [ 6 , 82 , 83 , 84 ]. Indeed, the uterus harbors a population of stem cells that can differentiate into myocyte, respiratory epithelial, neuronal, endothelial, hematopoietic, pancreatic, hepatic, adipocyte, and osteogenic lineages [ 85 ], as well as providing paracrine support for tissue repair [ 8 , 86 ].…”

“…Indeed, we successfully isolated a population of uterine stem cells from human endometrium, and found that they had greater proliferative, migratory and angiogenic capacities, with higher expression levels of pro-angiogenic factors, compared to human BM stem cells. Upon implantation into infarcted hearts, these pro-angiogenic cells maintained cardiac function, decreased infarct size and improved repair post-myocardial infarction, via increasing neo-vasculization and preserving viable myocytes [ 84 ]. This connection between uterine stem cells and increased angiogenesis is not surprising, as the uterus is a rare and abundant site of non-pathological angiogenesis in the post-development adult body.…”

“…Based on this logic, uterine stem cells could also be utilized in analogous ways as that of BM mesenchymal stem cells, as they are also able to migrate to the heart in response to injury. Indeed, the similarities in their migratory and cardiac repair capabilities have led to the possibility of intra-myocardial transplantation of uterine stem cells being a potential treatment option for heart disease, lowering the need for invasive surgical procedures [ 82 , 84 , 86 , 110 , 111 ].…”