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Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired
Yagna P R Jarajapu1, Sugata Hazra2, Mark Segal3
1Department of Pharmaceutical Sciences, College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Fargo, North Dakota, United States of America; Departments of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
Abstract:
We hypothesized that endothelial progenitor cells derived from individuals with diabetes would exhibit functional defects including inability to respond to hypoxia and altered paracrine/autocrine function that would impair the angiogenic potential of these cells. Circulating mononuclear cells isolated from diabetic (n = 69) and nondiabetic (n = 46) individuals were used to grow endothelial colony forming cells (ECFC), early endothelial progenitor cells (eEPCs) and isolate CD34+ cells. ECFCs and eEPCs were established from only 15% of the diabetic individuals tested thus directing our main effort toward examination of CD34+ cells. CD34+ cells were plated in basal medium to obtain cell-free conditioned medium (CM). In CM derived from CD34+ cells of diabetic individuals (diabetic-CM), the levels of stem cell factor, hepatocyte growth factor, and thrombopoietin were lower, and IL-1β and tumor necrosis factor (TNFα) levels were higher than CM derived from nondiabetic individuals (nondiabetic-CM). Hypoxia did not upregulate HIF1α in CD34+ cells of diabetic origin. Migration and proliferation of nondiabetic CD34+ cells toward diabetic-CM were lower compared to nondiabetic-CM. Attenuation of pressure-induced constriction, potentiation of bradykinin relaxation, and generation of cGMP and cAMP in arterioles were observed with nondiabetic-CM, but not with diabetic-CM. Diabetic-CM failed to induce endothelial tube formation from vascular tissue. These results suggest that diabetic subjects with microvascular complications exhibit severely limited capacity to generate ex-vivo expanded endothelial progenitor populations and that the vasoreparative dysfunction observed in diabetic CD34+ cells is due to impaired autocrine/paracrine function and reduced sensitivity to hypoxia.
Insights
Diabetic individuals have impaired endothelial progenitor cells (EPCs) with reduced angiogenic potential due to poor response to hypoxia and altered cell signaling. This limits their capacity for vascular repair.
Area of Science:
- Cardiovascular Biology
- Stem Cell Research
- Metabolic Disease Research
Background:
- Diabetes mellitus is associated with impaired vascular repair and increased cardiovascular risk.
- Endothelial progenitor cells (EPCs) play a crucial role in angiogenesis and vascular maintenance.
- Diabetic complications may stem from functional deficits in EPCs.
Purpose of the Study:
- To investigate functional defects in EPCs derived from diabetic individuals.
- To assess the impact of diabetes on EPC response to hypoxia and paracrine/autocrine function.
- To evaluate the angiogenic potential of diabetic EPCs.
Main Methods:
- Isolation and culture of endothelial colony forming cells (ECFCs), early endothelial progenitor cells (eEPCs), and CD34+ cells from diabetic and nondiabetic individuals.
- Analysis of cytokine and growth factor profiles in conditioned media (CM) from CD34+ cells.
- Assessment of CD34+ cell response to hypoxia (HIF1α upregulation).
- Evaluation of CM effects on nondiabetic CD34+ cell migration, proliferation, and vascular function (arteriole constriction/relaxation, cGMP/cAMP generation).
- Testing CM's ability to induce endothelial tube formation.
Main Results:
- Fewer EPCs (ECFCs, eEPCs) could be generated from diabetic individuals.
- Diabetic-derived CD34+ cell conditioned media (CM) showed lower levels of stem cell factor, hepatocyte growth factor, and thrombopoietin, and higher levels of IL-1β and TNFα.
- Diabetic CD34+ cells failed to upregulate HIF1α in response to hypoxia.
- Nondiabetic CD34+ cells exhibited reduced migration and proliferation towards diabetic-CM.
- Diabetic-CM impaired arteriole function and failed to induce endothelial tube formation.
Conclusions:
- Diabetic subjects exhibit a severely limited capacity to generate ex-vivo expanded EPC populations.
- Vasoreparative dysfunction in diabetic CD34+ cells is attributed to impaired autocrine/paracrine function and reduced sensitivity to hypoxia.
- These findings highlight a cellular mechanism contributing to the vascular complications observed in diabetes.
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