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Functional Heterogeneity of the Bone Marrow Vascular Niche
Author(s) -
Kopp HansGeorg,
Hooper Andrea T.,
Avecilla Scott T.,
Rafii Shahin
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.04964.x
Subject(s) - regeneration (biology) , bone marrow , haematopoiesis , cytopenia , progenitor cell , hematopoietic stem cell , cancer research , stem cell , microbiology and biotechnology , immunology , biology
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.