Swine bone marrow-derived multipotent adult stem cells and its application in swine hearts with postinfarction LV dysfunction.

摘要

Stem cell transplantation for cardiac repair has emerged as a novel therapeutic strategy to repair the damaged hearts. The mechanism of stem cell-mediated cardiac repair remains unclear, and may include stem cell-mediated angiogenesis, direct cell differentiation in endothelium or cardiocytes, fusion with endothelial cells or cardiocytes, and stem cell-mediated trophic factor (proangiogenic and anti-apoptotic) release. Multipotent Adult Progenitor Cells (MAPCs) were isolated from bone marrow of postnatal rodents and humans recently. Since MAPCs are derived from postnatal individuals and can differentiate into cells of the three germ layers at the single cell level, similar to what has been shown for embryonic stem cells (ESCs); they might be a great substitute of embryonic stem cells for many stem cell therapy applications, including, stem cell cardiac therapy.;First, we demonstrate that MAPCs can be derived from both postnatal and fetal swine bone marrow (BM). These isolated swine BM derived MAPCs have extensive self-renewal ability without cytogenetic abnormality. They can, at the single cell level, differentiate into cells of mesoderm, endoderm and neuroectoderm in vitro, characterized by the expression of lineage specific transcription factor and protein and some functional features.;Second, we demonstrated transplantation of pMultistem(TM), which were derived from one of our established swMAPCs lines, stabilizes bioenergetic and contractile function in the infarct zone (IZ) and border zone (BZ) followed by postinfarction LV dysfunction. Four weeks after pMultistem(TM) transplantation, we found improved BZ bioenergetics associated with significant recovery of CK-mt and CK-m isoform, improved BZ systolic thickening fraction, and improved LV ejection fraction. Only 0.35% donor cells could be detected 4 weeks after LAD ligation. The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was ∼3% and ∼2%, respectively. Patchy spared myocytes in IZ were found only in pMultistem(TM) transplanted hearts. Vascular density was significantly higher in both BZ and IZ of cell treated hearts compared to MI untreated hearts (p<0.05). Thus, allogeneic pMultisteMTM improved BZ energetics, regional contractile performance and global LV ejection fraction. These functional improvements may have resulted from paracrine effects including increased vascular density in the BZ and spared myocytes in IZ.