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Tatiana Salazar, James M Dominguez, Dung Nguyen, Maria Grant; Type 2 diabetes (T2D)-derived changes in the bone marrow induce hematopoietic progenitor cell dysfunction: Implications for diabetic retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2014;55(13):4917.
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Endothelial progenitor cells (EPC) are key players in vascular health and repair. In diabetes (DB), there is progressive endothelial dysfunction and development of vascular complications including DR. The source of this dysfunction may lie in the BM microenvironment. As DB progresses, the BM transitions from a hematopoietic-rich environment to increased adiposity and inflammation, negatively impacting EPC function. In this study, we set out to characterize the changes in the DB BM with the progression of DB on hematopoietic progenitors (HPC) and development of DR.
The T2D mouse model Leprdb (db/db) was used and the heterozygous, non-obese, non-DB form of the strain was used as a control (db/m). Mice were euthanized at 2, 6 and 9 months of DB. Colony forming ability was assessed through CFU assays. Cytokines were measured in the BM supernatant using bead protein arrays. HPC proliferation was measured through the use of a BRdU ELISA. Mouse retinas were isolated, fixed with 4% PFA and trypsin digested. Vascular retinas were then stained through PAS staining for enumeration of acellular capillaries (ac. caps).
Db/db showed increased HPC in the BM (p<0.05). When cultured in the CFC assays, cells from the early and mid-stage db/db (2 and 6 months) showed increased colony formation compared to db/m, particularly in granulocyte/macrophage progenitors (CFU-GM, p<0.001). However, with advanced DB (9 months), the situation is inverted (p<0.001). HPC proliferation was elevated early in DB, but diminished with the progression of the disease (p<0.01). In early DB, M-CSF concentrations were elevated in the BM (30.01 ng/mL vs. 16.04 ng/mL in db/m, p=0.02), but later changed to being lower than the db/m (23.85 ng/mL vs. 31.4 ng/mL, p=0.012). At 6 months, db/db showed reduced IL-10 and VEGF when compared to the db/m (8.3 ng/mL vs. 29.7 ng/mL and 27.1 ng/mL vs. 40.1 ng/mL). Db/db mice had higher numbers of ac. caps in the retina than db/m (6.5 ac. caps/mm2 vs. 4.9 ac. caps/mm2, p=0.02).
The early rise in BM progenitor proliferation could be a compensatory effect to the widespread vascular damage in DB or a result of higher production of pro-inflammatory macrophages, causing or aggravating the chronic inflammation seen in DB. With disease progression compensation is lost and progenitor function decreases promoting DR.
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