Umbilical cord blood stem cells for myocardial repair and regeneration.
Cardiovascular disease remains a major cause of morbidity and mortality with substantial economic cost. There remains a need for therapeutic improvement for patients refractory to revascularization and those who redevelop occlusions following revascularization. Early evidence linked age-associated reductions in the levels of circulating marrow-derived hematopoietic stem cells (HSC), characterized by expression of early HSC markers CD133 and CD34, with the occurrence of cardiovascular events and associated death. Heart tissue has the endogenous ability to regenerate through the activation of resident cardiac stem cells or through recruitment of a stem cell population from other tissues, such as bone marrow. A number of clinical trials have utilized patient-derived autologous bone marrow-derived cells or whole BM uncultured mononuclear cells (MNC) infused or injected locally to augment angiogenesis. In most cases of treating animal models with human cells, the frequency of stem cell engraftment, the subsequent number of newly generated cardiomyocytes and vascular cells, and the augmentation of endogenous microvascular collateralization, either by deposition, transdifferentiation, and/or by cell fusion, appear to be too low to explain the significant cardiac improvement. Initially, it was hypothesized that cell therapy may work by cell replacement mechanisms, but recent evidence suggests alternatively that cell therapy works by providing trophic support to the injured tissues. An alternative hypothesis is that the transplanted stem cells release soluble cytokines and growth factors (i.e., paracrine factors) that function in a paracrine fashion, contributing to cardiac repair and regeneration by inducing cytoprotection and neovascularization. Another hypothesis which may also be operative is that cell therapy may mediate endogenous regeneration by the activation of resident cardiac stem cell. Well-established clinical trials have used cord blood for the treatment of hematological malignances (e.g., leukemia, lymphoma, myeloma) and nonmalignancies (e.g., in born errors of metabolism, sickle cells anemia, autoimmune diseases), but further advances in other areas of regenerative medicine (e.g., cardiac repair) will directly benefit with the use of cord blood. These clinical outcomes demonstrate that effector cells may be delivered by an allogeneic approach, where strict tissue matching may not be necessary and treatment may be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.
Greco
Nicholas
N
Division of Hematology/Oncology, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. ngreco@clevelandcordblood.org
Laughlin
Mary J
MJ
D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D009203:Myocardial Infarction / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology