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Quantity and Control Culture of Diabetic Stem Cells Boosts Vascular Regenerative Potential

Review of “Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The use of endothelial progenitor cells (EPCs) isolated from diabetic patients in clinical vascular regenerative therapies requires optimized and simplified isolation and culture techniques to recuperate disease-induced functional deficits [1]. Previous research from the laboratory of Rica Tanaka (Juntendo University, Tokyo, Japan) identified a serum‐free quantity and control culture method (QQc) that restored lost functionality to peripheral blood EPCs isolated from human diabetic patients [2]. Furthermore, their subsequent study demonstrated that EPCs isolated and cultured using their strategy demonstrated improved vasculogenic and wound healing potency in a mouse model of diabetic wound healing [3].

As the isolation of therapeutically-relevant numbers of human peripheral blood EPCs remains challenging, the authors developed a QQc method for the serum‐free expansion of total peripheral blood mononuclear cells (PBMNCs) to generate an EPC-containing cell population fit for regenerative purposes [4-6]. In their recent STEM CELLS Translational Medicine article [7], Tanaka et al. now explore the therapeutic potential of their QQc-expanded PBMNCs from human diabetic patients through a comprehensive evaluation of their vasculogenic, anti‐inflammatory, and diabetic wound‐healing activity.

The authors isolated PBMNCs from human diabetic patients and then placed them under QQc culture for seven days, which comprised serum-free expansion media containing a simple combination of supportive growth factors and cytokines. In vitro evaluations by EPC colony-forming assays, fluorescence-activated cell sorting, EPC culture, tube forming assays with human endothelial cells, and RNA profiling and in vivo evaluations using a diabetic wound healing assay in Balb/c nude mice all suggested that QQc culture significantly enhanced the vasculogenic, anti‐inflammatory, and wound‐healing properties of PBMNCs isolated from human diabetic patients. Specifically, QQc culture supported the growth of EPCs and anti‐inflammatory pro‐angiogenic monocytes and T lymphocytes in PBMNC samples while drastically eliminating pro‐inflammatory and anti‐regenerative cells.

Overall, the authors report that the serum‐free quantity and control culture of PBMNCs from human diabetic patients represents a quick, simple, safe, and efficient approach to boost the vasculogenic, anti-inflammatory, and wound healing capacities of this easy-to-isolate cell source and thereby enhance associated clinical vascular regenerative therapies. The authors hope to address the limitations of their study, including the use of a small number of samples and animal models and the limited generalizability of results, to accelerate the clinical application of this exciting new advance.

For more on how the serum‐free quantity and control culture of diabetic stem cells may provide an optimal cell source for vascular regenerative therapy in human diabetic patients, stay tuned to the Stem Cells Portal!


  1. Jarajapu Yagna PR and Grant Maria B, The Promise of Cell-Based Therapies for Diabetic Complications. Circulation Research 2010;106:854-869.
  2. Tanaka R, Vaynrub M, Masuda H, et al., Quality-Control Culture System Restores Diabetic Endothelial Progenitor Cell Vasculogenesis and Accelerates Wound Closure. Diabetes 2013;62:3207.
  3. Tanaka R, Masuda H, Fujimura S, et al., Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells. STEM CELLS Translational Medicine 2018;7:428-438.
  4. Masuda H, Tanaka R, Fujimura S, et al., Vasculogenic Conditioning of Peripheral Blood Mononuclear Cells Promotes Endothelial Progenitor Cell Expansion and Phenotype Transition of Anti‐Inflammatory Macrophage and T Lymphocyte to Cells With Regenerative Potential. Journal of the American Heart Association;3:e000743.
  5. Kado M, Tanaka R, Arita K, et al., Human peripheral blood mononuclear cells enriched in endothelial progenitor cells via quality and quantity controlled culture accelerate vascularization and wound healing in a porcine wound model. Cell Transplantation 2018;27:1068-1079.
  6. Ohtake T, Kobayashi S, Slavin S, et al., Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice. Cell Transplantation 2018;27:520-530.
  7. Tanaka R, Ito-Hirano R, Fujimura S, et al., Ex vivo conditioning of peripheral blood mononuclear cells of diabetic patients promotes vasculogenic wound healing. STEM CELLS Translational Medicine 2021;10:895-909.