Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

Abstract

Autologous endothelial progenitor cell (EPC) therapy is commonly used to stimulate angiogenesis in ischemic repair and wound healing. However, low total numbers and functional deficits of EPCs make autologous EPC therapy ineffective in diabetes. Currently, no known ex vivo culture techniques can expand and/or ameliorate the functional deficits of EPCs for clinical usage. Recently, we showed that a quality‐quantity culture (QQc) system restores the vasculogenic and wound‐healing efficacy of murine diabetic EPCs. To validate these results and elucidate the mechanism in a translational study, we evaluated the efficacy of this QQc system to restore the vasculogenic potential of diabetic human peripheral blood (PB) CD34+ cells. CD34+ cells purified from PB of diabetic and healthy patients were subjected to QQc. Gene expression, vascular regeneration, and expression of cytokines and paracrine mediators were analyzed. Pre‐ or post‐QQc diabetic human PB‐CD34+ cells were transplanted into wounded BALB/c nude mice and streptozotocin‐induced diabetic mice to assess functional efficacy. Post‐QQc diabetic human PB‐CD34+ cell therapy significantly accelerated wound closure, re‐epithelialization, and angiogenesis. The higher therapeutic efficacy of post‐QQc diabetic human PB‐CD34+ cells was attributed to increased differentiation ability of diabetic CD34+ cells, direct vasculogenesis, and enhanced expression of angiogenic factors and wound‐healing genes. Thus, QQc can significantly enhance the therapeutic efficacy of human PB‐CD34+ cells in diabetic wounds, overcoming the inherent limitation of autologous cell therapy in diabetic patients, and could be useful for treatment of not only wounds but also other ischemic diseases. Stem Cells Translational Medicine 2018;7:428–438

Delivery of Human Stromal Vascular Fraction Cells on Nanofibrillar Scaffolds for Treatment of Peripheral Arterial Disease

“…Preclinical data showed that CD34 + cells represent a main subset of stem/progenitor cells in peripheral blood mononuclear cell transplants that potentiate neovascularization in the ischemic area (Schatteman et al, 2000), and improve blood perfusion (Li et al, 2010) and wound healing (Tanaka et al, 2018). In the present study, CD45 − /CD31 − /CD34 + comprised the majority of the SVF cells.…”

Regeneration-associated cells improve recovery from myocardial infarction through enhanced vasculogenesis, anti-inflammation, and cardiomyogenesis

“…Transplanted RACs initiated angiogenesis in host tissues in the same manner as in previously described ischemia disease models[21, 29, 30]. In vitro , rat QQMNC EPC-CFUs were increased, mostly with dEPC-CFUs, which are capable of forming “tube-like” structures.…”

“…In this regard, QQMNCs are considered a representative “regeneration-associated cell” (RAC) population for ischemia or regenerative organs. This therapeutic concept was evaluated by several animal experiments, involving hindlimb ischemia, acute ischemic kidney injury, and diabetic wound healing mouse models, which analyzed the potential of QQMNCs to induce recovery organ function[21, 29, 30].…”

Predictors of responders to mononuclear stem cell-based therapeutic angiogenesis for no-option critical limb ischemia

“…The number of transplanted human CD34 + cells appeared to have a strong correlation with the blood perfusion index in the severe combined immunodeficiency mouse model [23]. In addition, the increased number of transplanted CD34 + cells improved the chance of wound healing [32]. Previous clinical studies suggested thatCD34 + cells should be used as quality control for transplants, and a total CD34 + cell count over 10 5 /kg body weight seemed appropriate [33].…”