Abstract 1748: Diabetic Bone Marrow Microangiopathy Causes Marrow Hypoperfusion and Impoverishes the Stem Cell Niche of Linneg/Sca-1pos/c-kitpos Cells
Bone marrow (BM) homeostasis is maintained by interaction of stem cell (SC) with the vascular niche. Previously, we showed that diabetes (D) impairs SC trans-endothelial trafficking. Here, we evaluated the impact of microangiopathy on the SC niche. Further, we determined whether the vitamin B1 analogue Benfotiamine (BFT, 70mg/kg/day), which is a ROS scavenger, protects the BM from D. We studied streptozotocin-induced (STZ) type-1 D, type-2 D Lepr (db/db) and age-and strain-matched non-D mice (ND) (n = 6 to 10 per group). In the limb BM of both STZ and db/db, we observed microvessel rarefaction (histology) and reduction of MECA32pos endothelial cells (flow cytometry), which caused hypoperfusion of femur BM (assessed by fluorescent microspheres) (STZ: 0.17 ± 0.01 vs. 0.27 ± 0.1 mL/min/gm tissue in ND, p < 0.05; db/db: 0.18 ± 0.01 vs. 0.33 ± 0.1 mL/min/gm tissue in ND, p < 0.01). Morphometric evaluation of BM composition showed reduced marrow cellularity, fat accumulation and reduced bone density in both STZ and db/db. In ND, Linneg/Sca-1pos/c-kitpos cells (LSK, immunofluorescence) were scattered throughout the BM, their incidence predominating in the epiphysis and metaphysis, where clusters of 2–9 cells, mimicking SC niches, were located in the paratrabecular and perivascular areas. D reduced by nearly 2-fold and 3-fold, respectively, the number of individual and clustered LSK, especially in the paratrabecular location. Flow cytometry of BM MNC collected from the endosteal region showed reduced percentage of LSK cells in STZ (0.6 ± 0.1 vs 2.1 ± 0.6% of MNC in ND, p < 0.05). Assessment of SC distribution along an in vivo Hoechst 33342 (Hoe) dye perfusion gradient demonstrated a 3-fold decrease of Hoelow LSK, associated with a 2-fold increase in the number of Annexin Vhigh stained cells. BFT prevented microangiopathy, improved BM perfusion, and restored LSK abundance in endosteal and Hoelow regions (p < 0.01 vs vehicle for all comparisons). Results are the first to provide evidence that microangiopathy creates a detrimental environment for the SC niche, ultimately leading to exhaustion of primitive LSK cells. BFT prevents microangiopathy and SC impairment, thus opening new avenues for the treatment of D complications.