Decreased Circulating Progenitor Cell Number and Failed Mechanisms of Stromal Cell-Derived Factor-1α Mediated Bone Marrow Mobilization Impair Diabetic Tissue Repair

Abstract

OBJECTIVEProgenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing.RESEARCH DESIGN AND METHODSCutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points.RESULTSSignificantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin−/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2% lin−/ckit+/sca1+ vs. 13.5 ± 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin−/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0% vs. 11.9 ± 3% at day 7, P > 0.05; 73.0 ± 6.4% vs. 36.5 ± 7% at day 14, P < 0.05; and 88.0 ± 5.7% vs. 66.7 ± 5% at day 21, P > 0.05, respectively).CONCLUSIONSSuccessful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemia-mediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.

Effect of Stem Cell Therapy on Induced Diabetic Keratopathy in Albino Rat

“…In accordance it was documented that diabetic humans and animals exhibit fewer numbers of circulating progenitor cells (PCs) at rest and in response to ischemia. This can be refered to reduced ability of CD34 +ve endothelial PCs to proliferate, differentiate and integrate into the vessel (29).…”

Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M

“…Identification of such a macrophage-derived factor is a primary challenge in this field, because it will eventually turn into a therapeutic target in "poor mobilizer" conditions, such as diabetes. On the basis of observations that hyperglycemia promotes myelopoiesis (20) and that diabetes alters macrophage populations (21) and is associated with a defective CXCL12 switch (11,12), in the study reported here we examined the role of BM macrophages (BMMF) in diabetic SC mobilopathy. We found an excess of proinflammatory macrophages in the diabetic BM and that macrophage depletion restores mobilization.…”

“…In addition, because the BM is a reservoir of vascular regenerative cells, BM alterations may pave the way to multiorgan damage (2). On a molecular level, diabetes prevents the chemokine (C-X-C motif) ligand 12 (CXCL12) switch (11,12) (i.e., the suppression of intramarrow levels of the chemokine CXCL12 that normally allows stem cell mobilization) (13). Although a maladaptive response of the CXCL12-cleaving enzyme dipeptidyl peptidase-4 has been hypothesized (14), the exact mechanism perturbing a coordinated CXCL12 regulation in diabetes is unclear.…”

Fat Prospects for Healing Cutaneous Wounds: New Activities Under the Sheets

“…Cutaneous wound site multicellular competence and engagement is essential for normal cytokine/ chemokine/growth factor dynamics that produce dermal tissue homeostasis. However, cellular deficiencies and disruption in diabetic wounds compromise this process and also elicit impaired angiogenesis and neovascularization associated with abnormal endothelial cell functions and vascular endothelial growth factor and stromal cellderived factor 1 bioactivities, contributing to the diabetic wound healing problem (5,6). Recent evidence demonstrates that bone marrow-derived progenitor cells are correlated with new blood vessel formation in wounds (7,8).…”

“…Cutaneous injury mobilizes these progenitor cells from marrow, and resulting circulating progenitor cells then transport to injury sites, transmigrate into wounded tissue, and initiate repair functions, among them new vessel formation (7,9). While numbers of marrow-derived progenitors in diabetic and wild-type mice are relatively similar, reduced mobilized circulating progenitor cells are present in diabetic mice both before and after wounding (5). Harvesting marrow cells and adoptively transferring them, either topically or subcutaneously, into diabetic wounds overcomes impaired progenitor cell mobilization, injury homing, and migration.…”