Reversal of Diabetic Stem/progenitor Cell Mobilopathy by a Nonapeptide Antagonist of Leptin Receptor

Abstract

Adult bone marrow‐derived hematopoietic stem/progenitor cells (HSPCs) have the propensity of re‐endothelialization and revascularization following ischemic vascular damage. Diabetes is associated with severe impairment in pharmacological mobilization of HSPCs by granulocyte‐colony stimulating factor (G‐CSF) or plerixafor. Leptin, an adipocyte‐derived hormone, elicits pro‐hematopoietic functions by acting on leptin receptor (LepR). LepR is expressed in HSPCs. We have previously reported that leptin‐LepR pathway negatively modulates HSPC mobilization by G‐CSF or plerixafor, and that LepR‐antagonist, PESLAN‐1 exacerbated G‐CSF‐ or plerixafor‐induced mobilization. However, LepR‐antagonism is known to increase the food intake and body weight. In this study we tested the efficacy of a nonapeptide antagonist of LepR, allo‐aca, which cannot cross the blood brain barrier, in reversing the diabetic mobilization dysfunction. The study was performed in age‐matched control and streptozotocin (STZ)‐induced diabetic mice (C57Bl/6). Mobilization induced by G‐CSF (125 μg/Kg, s.c., twice a day, 4 days) or plerixafor (5 mg/Kg, s.c., single dose) was evaluated by flow‐cytometric enumeration of circulating Lineage−Sca‐1+cKit+ (LSK) cells, and by colony forming unit (CFU) assay. Effects of allo‐aca (0.3 mg/Kg/day, s.c., 28 days) (Peptides International) or PESLAN‐1 (10 mg/Kg, s.c., once in two days for 18 days) were evaluated on body weight, basal/mobilized levels of LSK cells and CFUs. No significant change in body weight was observed in control or diabetic mice treated with allo‐aca, in contrast PESLAN‐1 caused gradual increase in body weight of control mice (14% vs untreated control, P<0.01). In control mice (n=7), allo‐aca treatment has no effect on basal mobilization of LSK cells but it robustly potentiated G‐CSF‐ or plerixafor‐induced mobilization of LSK cells (6.39±1.05‐ and 1.39±0.1‐fold higher (P<0.05), respectively, than untreated). Along similar lines, pretreatment with PESLAN‐1 potentiated LSK mobilization by G‐CSF (n=7, P<0.001) or plerixafor (n=6, P<0.05). In agreement with our previous findings, LSK mobilization was impaired in response to G‐CSF‐ or plerixafor (n=6 to 8, P<0.01 vs control) in diabetic mice, which was reversed by allo‐aca treatment (8.05±1.83‐ and 6.68±1.16‐fold higher (n=7, P<0.05), respectively, than untreated). Consistent with flow cytometric enumeration, CFUs derived from G‐CSF‐mobilized cells were decreased in STZ‐diabetic mice compared to control (n=6 to 8, P<0.05 vs control) and treatment with allo‐aca increased CFUs in the circulating cells in diabetic mice in response to G‐CSF (n=6, P< 0.05 vs allo‐aca untreated). Collectively, these results suggest that the novel nonapeptide‐antagonist of LepR, allo‐aca, is a promising molecule for reversing diabetic HSPC mobilopathy without inducing weight gain.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.