Functional Heterogeneity of the Bone Marrow Vascular Niche

Abstract

Sinusoidal endothelial cells (SECs) comprise the platform where trafficking into and out of the BM occurs and where hematopoietic stem and progenitor cells (HSPC) harbor and receive cues for self-renewal, survival, and differentiation. Therefore, SECs are referred to as a bone marrow vascular niche (BMVN). Hematopoietic regeneration has been shown to occur only with concurrent angiogenic regeneration. However, there are still not sufficient means to identify and isolate SECs, therefore the “niche endothelial cell” remains incompletely characterized. VEGF-receptor-3 (VEGFR3) is expressed exclusively by the SECs, while Sca1 and Tie2 are only expressed on the VEGFR3− arteriolar endothelium. We previously demonstrated the importance of vascular recovery in hematopoietic regeneration from myelosuppression due to cytotoxic agents or whole-body irradiation. Therefore to establish the functional importance of SECs, the mechanisms underlying BMVN regeneration were examined utilizing a 5-fluorouracil (5-FU) myelosuppression model of vascular damage. Injection of antibodies against murine VEGFR-1 and -2 had no significant effect on hemangiogenic recovery. However, when soluble VEGFR-1, a decoy receptor for VEGF-A and PlGF, was injected after 5-FU, both angiogenic remodeling and regeneration of megakaryopoiesis were delayed. In conclusion, we show that the bone marrow vasculature comprises heterogeneous compartments. SECs are distinguished from arterioles by unique immunophenotypes. Regeneration of damaged SECs is the rate-limiting step in hematopoietic regeneration from myelosuppressive therapy. Novel, high-efficiency VEGF-binding drugs in combination with chemotherapeutic agents may lead to cases of prolonged cytopenia.

Bone Marrow Regeneration Promoted by Biophysically Sorted Osteoprogenitors From Mesenchymal Stromal Cells

“…Overall, we found modest improvements in median survival times (12,17, and 17 days for passage 3, 6, and 9 MSCs, respectively; supplemental online Fig. 4B) and reduced weight loss in MSCinfused mice compared with untreated mice (∼30% vs. ∼40% loss, respectively, within 5 days; supplemental online Fig.…”

“…It is plausible that those progenitor cell subpopulations could thus be more therapeutically efficacious than uncommitted, multipotent MSCs (i.e., stem cells) for some translational applications. Recent investigations of the physiological roles of MSCs and their progenitors within the marrow have provided insight into their different possible therapeutic values [5,[13][14][15][16][17]. Literature observations have alluded to a connection between BM-derived MSCs with high osteogenic activity and the capabilities for microenvironmental repair as well as HSC support, both of which critical for BM homeostasis.…”

PDGFR Signaling Blockade in Marrow Stroma Impairs Lung Cancer Bone Metastasis

“…Currently, sunitinib is under intensive investigation in a variety of other cancers including breast, colorectal, and non-small cell lung cancer (18). The major targets VEGFR-1 to -3 are largely expressed in ECs; therefore, sunitinib elicits a potent antiangiogenic effect and might influence BM homeostasis (19)(20)(21). PDGFR has been shown to be crucial for pericyte maintenance and its inhibition synergizes with VEGFR blockade to impair tumor growth (22).…”

Clonal precursor of bone, cartilage, and hematopoietic niche stromal cells

“…This niche, or microenvironment, contains diverse cell types that, with their secreted products, are required by hematopoietic stem cells (HSCs) to generate the full array of blood and immune cells (1,2). The cellular constitution of niches is poorly understood but is believed to include osteoblasts, endothelial cells, glial cells, vascular pericytes, adipocytes, fibroblasts, and nestinexpressing mesenchymal stromal cells (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The existence of HSC niches is substantiated by evidence that HSCs continuously enter and exit the bone marrow from the peripheral circulation and that direct HSC transplants engraft in numbers that correlate with the number of HSCs in circulation (14,15).…”