Development of the Fetal Bone Marrow Niche and Regulation of HSC Quiescence and Homing Ability by Emerging Osteolineage Cells
Süleyman Coşkun,
Hsu Chao,
Hema Vasavada,
Kartoosh Heydari,
Naomi Gonzales,
Xin Zhou,
Benoit de Crombrugghe,
Karen K. Hirschi
Affiliations
Süleyman Coşkun
Yale Cardiovascular Research Center, Department of Internal Medicine, Vascular Biology and Therapeutics Program and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA
Hsu Chao
Children’s Nutrition Research Center and Center for Cell and Gene Therapy, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Hema Vasavada
Yale Cardiovascular Research Center, Department of Internal Medicine, Vascular Biology and Therapeutics Program and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA
Kartoosh Heydari
Cell Sorter Core Facility, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06511, USA
Naomi Gonzales
Children’s Nutrition Research Center and Center for Cell and Gene Therapy, Departments of Pediatrics and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Xin Zhou
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Benoit de Crombrugghe
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Karen K. Hirschi
Yale Cardiovascular Research Center, Department of Internal Medicine, Vascular Biology and Therapeutics Program and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA
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.
