Development of the Fetal Bone Marrow Niche and Regulation of HSC Quiescence and Homing Ability by Emerging Osteolineage Cells

• Published in: Cell reports (Cambridge) 2014-10, Vol.9 (2), p.581-590
• Main Authors: Coşkun, Süleyman, Chao, Hsu, Vasavada, Hema, Heydari, Kartoosh, Gonzales, Naomi, Zhou, Xin, de Crombrugghe, Benoit, Hirschi, Karen K.
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow - blood supply; Bone Marrow - embryology; Cell Lineage; Cell Proliferation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - physiology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Osteogenesis; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Sp7 Transcription Factor; Stem Cell Niche; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.09.013

Hematopoietic stem cells (HSCs) reside within a specialized niche where interactions with vasculature, osteoblasts, and stromal components regulate their self-renewal and differentiation. Little is known about bone marrow niche formation or the role of its cellular components in HSC development; therefore, we established the timing of murine fetal long bone vascularization and ossification relative to the onset of HSC activity. Adult-repopulating HSCs emerged at embryonic day 16.5 (E16.5), coincident with marrow vascularization, and were contained within the c-Kit+Sca-1+Lin− (KSL) population. We used Osterix-null (Osx−/−) mice that form vascularized marrow but lack osteolineage cells to dissect the role(s) of these cellular components in HSC development. Osx−/− fetal bone marrow cells formed multilineage colonies in vitro but were hyperproliferative and failed to home to and/or engraft transplant recipients. Thus, in developing bone marrow, the vasculature can sustain multilineage progenitors, but interactions with osteolineage cells are needed to regulate long-term HSC proliferation and potential. [Display omitted] •Murine fetal long bones have a perfused vasculature beginning at E16.5•HSCs reside within vascularized regions of fetal bone marrow as early as E16.5•The fetal bone marrow vascular niche alone cannot support long-term HSCs•Osteolineage cells within fetal bone regulate HSC quiescence and homing ability HSCs reside within a specialized niche where interactions with vasculature, osteoblasts, and stromal components regulate their self-renewal and differentiation. Coşkun et al. now map fetal bone marrow niche development and examine the impact of its cellular components on HSC phenotype and function.