Wound healing is a well-regulated complex process that occurs as a cellular response to injury and consists of four phases: hemostasis, inflammation, proliferation, and remodeling (1). Many factors, such as diabetes and obesity, interfere with these stages and lead to wound healing defect. Diabetes affects approximately 170 million people worldwide, including 20.8 million in the U.S., and by 2030 these numbers are projected to double (2). Impaired wound healing is a major clinical problem in patients with diabetes and is the leading cause of lower-extremity amputation and comorbidity associated with diabetes. Diabetic skin ulcers are estimated to occur in 15% of all patients with diabetes and 84% of all diabetes-related lower-leg amputations (3,4). Despite current treatments, one in four patients with diabetic ulcers will have a foot amputation. Therefore, new treatment strategies for healing diabetic skin ulcers are highly needed. Impaired or delayed wound healing in diabetes is characterized by impaired angiogenesis and vasculogenesis (5). Adult bone marrow progenitor cells, bone marrow–derived endothelial progenitor cells (BMPCs), can home to injured tissue and participate in the tissue repair regeneration process. However, in diabetes, BMPCs are dysfunctional (defective recruitment and reduced survival and proliferation) (6). The mechanism of bone marrow cell dysfunction in diabetes is not yet fully understood. Endoplasmic reticulum (ER), a multifunctional organelle involved in lipid synthesis, calcium homeostasis, protein folding, and maturation, responds to stress (diabetes, oxidative stress, and disturbance in calcium homeostasis) by inhibiting protein translation and activating protein chaperones via a process called unfolded protein response (UPR) (7,8). The UPR activates signaling pathways through three major ER resident proteins: the protein kinase RNA-like ER kinase (PERK), the inositol-requiring enzyme 1 (IRE1), and the activating transcription factor (ATF6) (9). IRE1 through its endonuclease activity cleaves the mRNA encoding the transcription factor X-box binding protein 1 (XBP1) to splice XBP1 (sXBP1) responsible for the upregulation of various genes involved in the UPR signaling to limit protein misfolding in the ER (9). In addition to XBP1 splicing, IRE1α also cleaves other mRNAs of the ER membrane and microRNAs (miRNAs) (10), leading to their degradation through regulated IRE1α-dependent decay (RIDD) (11,12). We and others have shown that ER stress plays a major role in angiogenesis impairment (13) and wound healing delay in diabetes (14,15).
In the context of diabetes, Wang et al. (16) proposes a new role of the ER stress sensor IRE1α in a wound healing model through the modulation of miRNAs and the improvement of BMPC function, independent of XBP1 activation. One of the challenges of the ER stress response in diabetes and other pathological situations is the fact that it is difficult to distinguish between the protective pathways and the detrimental pathways once the UPR response is triggered. Therefore, the study by Wang et al. is of interest as it is setting the ground for new ways to differentiate between the apoptotic and the adaptive pathways by focusing on the IRE1α endonuclease activity, independent of the classic function of sXBP1. These findings open new opportunities to target the ER stress and particularly IRE1α in stem cells to recue wound healing in type 2 diabetes. Wang et al. (16) reported that the expression and activity of the IRE1 was the only ER stress sensor reduced in diabetic BMPCs, which is responsible for the loss of their function independent of XBP1. These results suggest the particular role played by IRE1α in the functional disturbance of BMPCs found in diabetes. In contrast, a very recent report (17) showed that BMPCs isolated from type 2 diabetic mice exhibited an increase in all ER stress sensors, including the active form of IRE1 and sXBP1. Further studies are needed to clarify the discrepancy between the two studies. Moreover, Wang et al. (16) proposed miR-200 and miR-466 as underlying mechanisms by which IRE1α regulates BMPC function in diabetes. Interestingly, IRE1α overexpression was able to increase angiopoietin-1 expression, a potent angiogenic factor in diabetic BMPCs, and restore BMPC function. Moreover, using a mouse model of wound healing, the authors confirmed the in vitro data by demonstrating that cell therapy using diabetic BMPCs overexpressing IRE1α improved and accelerated the wound closure. This study not only showed the in vitro and in vivo contribution of IRE1α controlling diabetic BMPC function but also delineated the mechanism by which IRE1α specifically through its RIDD activity downregulated miRNAs (miR-200 and miR-466), regulating BMPC dysfunction and wound healing delay in diabetes. The discovery of miRNAs in 1993 (18) advanced our knowledge on gene regulation, the involvement of miRNAs in physiological processes, and particularly miRNA modulation in many diseases, including diabetes. In fact, the study by Wang et al. (16) established the link between diabetes, ER stress, miRNAs, and angiogenesis defect in a model of wound healing. In line with these results, a previous study showed that miR-200c (a member of the miR-200 family) was found to be upregulated in arteries from mice and patients with diabetes and appeared to be the new mediator of diabetic endothelial dysfunction (19). Thus, it is important to determine the status of IRE1α activity (sXBP1 vs. mRNA/miRNA degradation) in other cells/tissues involved in angiogenesis and tissues regeneration in type 2 diabetes. Recently, it has become evident that miRNAs are important regulators of cellular UPR response (20). One can speculate that increased expression levels of miR-200 and miR-446 in diabetic bone marrow cells would impact IRE1α activity, leading to BMPC dysfunction. More studies are needed to clarify this point.
In summary, the study by Wang et al. (16) outlined the importance of IRE1α as a crucial factor regulating the fate/function of BMPCs involved in angiogenesis and tissue repair via modulating miRNA expression levels (Fig. 1). Further studies are needed to determine the mechanism that inhibits IRE1α activity in diabetic BMPCs and the potential of expanding these findings to other complications related to diabetes, such as cardiovascular complications, as well as validating these findings in preclinical/translational models. The work of Wang et al. represents a promising avenue for tissue repair and regeneration and opens new opportunities to specifically target IRE1α in diabetes.
See accompanying article, p. 177.
Funding. The authors acknowledge the support from the East Virginia Medical School Fund.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.