Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations

Abstract

IntroductionPathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity.MethodsIn this study, we examined the impact of diabetes on the murine ASC niche as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single-cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting.ResultsOur results demonstrate that diabetes alters the ASC niche in situ and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single-cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth.ConclusionsPerturbations in specific cellular subpopulations, visible only on a single-cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in patients with diabetes may be limited and that interventions to improve cell function before application are warranted.

Delivery of Mesenchymal Stem Cells in Biomimetic Engineered Scaffolds Promotes Healing of Diabetic Ulcers

“…Our data suggest that use of the proper matrix components, at physiological density and configuration, promotes MSC survival and function to promote wound healing. Interestingly, diabetes is associated with diminished subpopulations of MSCs, suggesting that diabetic ulcers may be amenable to therapies that restore MSC numbers and/or function [37,38]. The stem cell niche provides a microenvironment conducive for stem cell survival and maintenance of multipotency.…”

Progenitor Cell Dysfunctions Underlie Some Diabetic Complications

“…8 Stem cells and progenitor cells are dysfunctional at both a population-wide and a single-cell level in diabetes. 14 It would be expected, therefore, that correcting or treating diabetes will restore the function of these progenitors and prevent further tissue complications. However, this is not always the case.…”

“…104 Similarly, bone marroweMSC and ASC transplants have been tested for the modulation of diabetic nephropathy and for the treatment of nonhealing diabetic wounds resulting from neuropathy and microvasculopathy. 14,105,106 This section details the various approaches of using autologous stem cells for treating diabetic complications.…”

Stem cells and chronic wound healing: state of the art

“…However, the diabetic status of the patients in this trial did not correlate with response, 68 which is surprising given recent studies showing diabetes impairs the ability of ASCs to promote neovascularization (via subpopulation depletion). 69 Not all studies have shown that chronic systemic disease impairs stem cell functionality. Smadja et al 70 noted that BM-MSCs harvested from CLI patients and healthy controls demonstrate similar proangiogenic effects when transplanted into CLI-induced mice.…”