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.
Highlights
Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing
adipose-derived mesenchymal stem cell (ASC) promotion of neovascularization To determine the impact of diabetes on the ASC niche in situ, the transcriptional profiles of type 2 diabetes mellitus (DM2) and WT murine fat pads were analyzed
Both ASC groups localized around the human umbilical vein endothelial cells (HUVECs), consistent with their perivascular nature, the DM2 ASCs supported significantly less HUVEC tubule formation compared with WT ASCs (16.9 versus 27.1 tubules per HPF; P = 0.001) (Figure 1C), indicating that diabetic ASCs possess a reduced stimulatory capacity
Summary
Pathophysiologic 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, it remains unclear whether diabetes impairs their functional and therapeutic capacity. Diabetes has been linked to impairments in the functionality of diabetic endothelial progenitor cells (EPCs) and resident tissue fibroblast in vitro [2,3]. Cell-based therapies, in particular, represent an appealing treatment paradigm, as they potentially contribute both cytokines and a cellular framework to the tissue regeneration process. In support of this approach, multiple cell-based products delivering fibroblasts or fibroblast-keratinocyte mixtures have a proven clinical efficacy for the treatment of diabetic wounds [6]. Advanced biomaterials are being developed to optimize cell survival and functionality within the harsh wound environment [7,8,9]
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