Hematopoietic Stem Cell Colonization of Fetal Bones is Controlled by the Integrity and Oxidative Status of the Developing Stromal-Vascular Niches

Abstract

Hematopoietic stem cell (HSC) maintenance throughout life and engraftment after transplantation during anticancer treatment, depend on support from various bone marrow (BM) niche compartments. Here, by studying physiological homing of fetal HSCs, we show the critical requirement of balanced crosstalk within the multi-component BM niche for enabling HSC-lodgment. Transgene-induced over-production of VEGF by skeletal progenitor cells elicited stromal and endothelial hyper-activation, profoundly impacting the stromal-vessel interface and vascular architecture. Concomitantly, HSC seeding, settlement and survival were drastically impaired. Transcriptome-profiling, flow-cytometry and high-resolution imaging indicated alterations in peri-/endothelial characteristics, vascular permeability, and cellular metabolism, associated with a higher oxidative status and increased oxidative stress within the VEGF-enriched BM-environment. Thus, developmental HSC-homing to bone is controlled by local inter-niche communication regulating stromal-vascular integrity and theoxidative and metabolic milieu.Since irradiation of adult mice also induced stromal VEGF-expression and similar osteo-angiogenic niche changes, our findings can contribute to improving stem cell therapy.