Progenitor Cell Dysfunctions Underlie Some Diabetic Complications

Abstract

Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications. Diabetes is characterized by insulin resistance and hyperglycemia, and affects a diverse array of cells, leading to a myriad of tissue complications. These include, but are not limited to, cardiac arrest, stroke, nephropathy, retinopathy, and non-traumatic lower limb amputations.1 Results from randomized clinical trials indicate that adequate glycemic control in diabetic patients reduces the risk of developing one or several of these complications. 2e4 The Diabetes Control and Complications Trial reports a reduction in the development or progression of diabetic nephropathy (50% reduction), neuropathy (60% reduction), and retinopathy (76% reduction) after intensive glycemic control. However, 33% of Americans with diabetes remain undiagnosed, approximately 12% of US adults with diabetes exhibit poor glycemic control, and different medical organizations recommend different glycemic targets, increasing the occurrence of diabetic complications.

Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia–Reperfusion Injury

“…Moreover, tissue-specific progenitor cellssuch as endothelial and cardiac progenitor cellshave similar glucose uptake and HK2 expression. Their dysfunction in diabetes is likely driven by HK2-linked glycolytic overload and also contributes to the development of diabetic complications [31].…”

High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu

“…The experiments confirmed the existence of cardiac progenitor cells expressing c‐kit, sca‐1, GATA‐4, GATA‐5, Mef2C, and NKx2.5 . Various scientific experiments revealed that diabetic condition affects the dynamic cardiac c‐kit + cells (CPCs) . Considering the paracrine pro‐angiogenic capacity and transdifferentiate into endothelial‐ and pericyte‐like cells, it is believed that CPCs take part in favour of vascularization, holding great promise for restoration of different tissues during injuries .…”

“…8 Various scientific experiments revealed that diabetic condition affects the dynamic cardiac c-kit + cells (CPCs). [9][10][11][12] Considering the paracrine pro-angiogenic capacity and transdifferentiate into endothelial-and pericyte-like cells, it is believed that CPCs take part in favour of vascularization, holding great promise for restoration of different tissues during injuries. [13][14][15] The transdifferentiation into endothelial-and pericyte-like cells is initiated by expressing cell distinct markers such as vWF (Von Will brand factor), CD31 (Platelet endothelial cell adhesion molecule [PECAM-1]), NG 2 (neural/glial antigen 2), and α-SMA (alpha smooth muscle actin), respectively.…”

Transmembrane Stem Cell Factor Protein Therapeutics Enhance Revascularization in Ischemia without Mast Cell Activation

“…Diabetic patients in particular have reduced recruitment of stem cells to ischemic regions, circulating endothelial progenitor cells and endothelial cell function 46,47 . We examined the expression of SCF/tmSCF in skin samples from diabetic and non-diabetic patients to assess differences.…”