Heart infarct in NOD‐SCID mice: Therapeutic vasculogenesis by transplantation of human CD34 ⁺ cells and low dose CD34 ⁺ KDR ⁺ cells

Abstract

Hematopoietic (Hem) and endothelial (End) lineages derive from a common progenitor cell, the hemangioblast: specifically, the human cord blood (CB) CD34+KDR+ cell fraction comprises primitive Hem and End cells, as well as hemangioblasts. In humans, the potential therapeutic role of Hem and End progenitors in ischemic heart disease is subject to intense investigation. Particularly, the contribution of these cells to angiogenesis and cardiomyogenesis in myocardial ischemia is not well established. In our studies, we induced myocardial infarct (MI) in the immunocompromised NOD-SCID mouse model, and monitored the effects of myocardial transplantation of human CB CD34+ cells on cardiac function. Specifically, we compared the therapeutic effect of unseparated CD34+ cells vs. PBS and mononuclear cells (MNCs); moreover, we compared the action of the CD34+KDR+ cell subfraction vs. the CD34+KDR- subset. CD34+ cells significantly improve cardiac function after MI, as compared with PBS/MNCs. Similar beneficial actions were obtained using a 2-log lower number of CD34+KDR+ cells, while the same number of CD34+KDR- cells did not have any effects. The beneficial effect of CD34+KDR+ cells may mostly be ascribed to their notable resistance to apoptosis and to their angiogenic action, since cardiomyogenesis was limited. Altogether, our results indicate that, within the CD34+ cell population, the CD34+KDR+ fraction is responsible for the improvement in cardiac hemodynamics and hence represents the candidate active CD34+ cell subset.

Glucose tolerance is negatively associated with circulating progenitor cell levels

“…While CD34 is an adhesion molecule expressed mainly on haematopoietic stem cells, KDR (also known as type 2 vascular endothelial growth factor receptor) is a typical endothelial marker. In support of the hypothesis that CD34 + KDR + cells correspond to EPCs, it should be noted that freshly isolated human CD34 + KDR + cells showed vascular healing properties in animal models of coronary and peripheral artery disease [31,32]. However, the simple evaluation of progenitor cells by flow cytometry implies the conceptual abstraction that antigenic phenotypes correspond to functional phenotypes, which is not always true: thus it is likely that CD34 + KDR + cells are a mixed population that includes EPCs.…”

Organ-injury-induced reactivation of hemangioblastic precursor cells

“…In addition, intrarenal injection of culture modified bone marrow-derived angiogenic cells reduced endothelial injury in experimental glomerulonephritis. 43 Thus, the vasculogenic potential of bone marrow-derived cells, previously shown in heart infarct or retinal neovascularization, 44,45 can be demonstrated in injured kidneys.…”

Development of Serum-Free Quality and Quantity Control Culture of Colony-Forming Endothelial Progenitor Cell for Vasculogenesis

“…ϩ or CD133 ϩ cells in umbilical cord blood (CB), bone marrow (BM), or peripheral blood (PB), previously defined as hematopoietic stem/progenitor cells, also serve as the enriched source of endothelial progenitor cells (EPCs) [1,2], inducing neovascularization for functional recovery from ischemic injury [3][4][5][6][7][8][9][10]. Particularly autologous CD34 ϩ or CD133 ϩ stem/ progenitor cells have been therapeutically transplanted in patients with severe ischemic heart or limb diseases, and these initial clinical experiences indicate the safety and feasibility as well as the effectiveness of cell-based therapy [3,[11][12][13][14][15][16][17][18][19].…”