Functional impairment of bone marrow progenitor cells in diabetes mellitus

1. Functional impairment of bone marrow progenitor cells in diabetes mellitus Nature Reviews Endocrinology 10, 379 (2014);

2. Introduction • While diabetes affects many aspects of human physiology, cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients • Specifically, diabetes causes dysfunction of the mature endothelium and impaired neovascularization in response to ischemia • It is evidenced by the reduced growth of collateral coronary vessels after acute myocardial infarction and the poor clinical outcomes associated with diabetic peripheral arterial disease

3. Introduction • In the absence of diabetes, neovascularization in response to ischemic injury progresses partially through the recruitment of bone marrow-derived progenitor cells into ischemic tissues via the circulation, a process termed vasculogenesis • In this study, bone marrow-derived mesenchymal progenitor cells (MPCs) that have previously been shown to be important for new blood vessel formation were examined

4. Research Design And Methods • Type 1 diabetes was induced in wild type mice with five consecutive daily injections of streptozotocin in sodium citrate • Two and four weeks after the last injection, blood glucose levels were assessed using a glucometer • Mice with capillary blood glucose levels <400 g/dL were excluded

5. Results • The researchers had previously identified a subset of progenitor cells in the bone marrow that support vasculogenesis and mobilize into circulation in response to peripheral tissue ischaemia • Reduced levels of circulating progenitor cells have been reported in patients with diabetes mellitus • This suggests that deficiency of these cells could contribute to the pathogenesis of complications associated with this disease

6. Results • The scientists demonstrated impaired vasculogenic function of diabetic bone-marrow-derived mesenchymal progenitor cells (BM-MPCs) in vivo and in vitro • An effect that was not reversed when glucose homeostasis levels in the mice were normalized, suggesting that these cells retained irreversible ‘diabetic memory’

7. Results • Using a novel technique that combined single-cell transcriptional analysis and machine learning, the scientists also identified two distinct populations of BM-MPCs that were depleted in diabetic mice compared with wild-type mice • These subsets expressed high levels of vasculogenesis-related genes, which suggests that the depletion of these cells might be involved in impairment of neovascularization in diabetes mellitus

8. Conclusion • The results suggest that dysfunction at the cellular level may compromise the mobilization and function of bone marrow-derived MPCs in diabetes • Also, the study demonstrates that these defects are irreversible • This suggests that cell-based therapeutics using autologous cells may be unlikely to succeed in correcting the effects of prolonged glucose exposure and impact the phenomenon of metabolic memory

9. Conclusion • Additional studies of these distinct subpopulations of BM-MPCs will be required to prove the functional differences suggested by their gene expression • These data suggest that autologous stem cell-based therapies in diabetic patients may be limited by intrinsic deficits in important progenitor cell populations • Also, new strategies focusing on healthy (non-diabetic) progenitor cells may be required