Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration

Abstract

Diabetes mellitus is a global health problem that results in multiorgan complications leading to high morbidity and mortality. Until recently, the effects of diabetes and hyperglycemia on the bone marrow microenvironment-a site where multiple organ systems converge and communicate-have been underappreciated. However, several new studies in mice, rats, and humans reveal that diabetes leads to multiple bone marrow microenvironmental defects, such as small vessel disease (microangiopathy), nerve terminal pauperization (neuropathy), and impaired stem cell mobilization (mobilopathy). The discovery that diabetes involves bone marrow-derived progenitors implicated in maintaining cardiovascular homeostasis has been proposed as a bridging mechanism between micro- and macroangiopathy in distant organs. Herein, we review the physiological and molecular bone marrow abnormalities associated with diabetes and discuss how bone marrow dysfunction represents a potential root for the development of the multiorgan failure characteristic of advanced diabetes. The notion of diabetes as a bone marrow and stem cell disease opens new avenues for therapeutic interventions ultimately aimed at improving the outcome of diabetic patients.

Keywords: Complications; Regeneration; Stem cells.

Figure 1.

The complex cellular and noncellular components of the bone marrow stem cell niche. Green and red boxes highlight the osteoblastic and vascular niches, respectively. Abbreviations: HSC, hematopoietic stem cell; HSPG, heparan sulphate proteoglycan; MSC, mesenchymal stem cells.

Figure 2.

Representative histopathologic features of the human diabetic bone marrow. (A, D): The entire biopsies from a control patient (A) and a diabetic (D) patient show reduced trabecular bone and increased marrow fat. (B–F): Immunoperoxidase CD34 (brownish) labeling in sections of human bone marrow (BM) documenting small individual progenitor cells ([C] and [F], black arrows) and the endothelial lining of capillaries and sinusoids (red arrowheads). An abnormally large paratrabecular sinusoid in a diabetic fatty BM is shown in (E), as part of the diabetic BM microangiopathy. Scale bars = 50 µm in (B) and (E) and 20 µm in (C) and (F).

Figure 3.

Hierarchical organization of hematopoietic stem cells (HSCs) and EPCs. The relationships between BM HSCs and various EPCs and how the latter reach the bloodstream are shown. The figure depicts the interplay between EPC phenotypes in the processes of angiogenesis. Abbreviations: BM, bone marrow; EC, endothelial cell; EOC, endothelial outgrowth cell; EPC, endothelial progenitor cell.

Figure 4.

The EPC CFA used to define the hematopoietic stem cell/EPC hierarchy. Representative immunofluorescent staining of the two colony-forming EPC types is shown. Red color fluorescence indicates acetylated LDL uptake, and green color fluorescence shows isolectin B4 bindings. The double positivity indicates endothelial lineage cells. Abbreviations: CF, colony-forming; CFA, colony-forming assay; EC, endothelial cell; EPC, endothelial progenitor cell; nCF, non-colony-forming assay.