Tissue stem cells are hierarchically organized. Those that are most primitive serve as key drivers of regenerative response but the signals that selectively preserve their functional integrity are largely unknown. Here, we identify a secreted factor, Semaphorin 4A (Sema4A), as a specific regulator of myeloid-biased hematopoietic stem cells (myHSC), which are positioned at the top of the HSC hierarchy. Lack of Sema4A leads to exaggerated myHSC (but not downstream “balanced” HSC) proliferation after acute inflammatory stress, indicating that Sema4A enforces myHSC quiescence. Strikingly, aged Sema4A knock-out myHSC expand but completely lose reconstitution capacity. The effect of Sema4A is non cell-autonomous, since upon transplantation into Sema4A-deficient environment, wild-type myHSC excessively proliferate but fail to engraft long-term. Sema4A constrains inflammatory signaling in myHSC and acts via a surface receptor Plexin-D1. Our data support a model whereby the most primitive tissue stem cells critically rely on a dedicated signal from the niche for self-renewal and life-long persistence.
Toghani, Dorsa and Zeng, Sharon and Mahammadov, Elmir and Crosse, Edie and Seyedhassantehrani, Negar and Burns, Christian and Gravano, David and Radtke, Stefan and Kiem, Hans-Peter and Rodriguez, Sonia and Carlesso, Nadia and Pradeep, Amogh and Wilson, Nicola and Kinston, Sarah and Göttgens, Berthold and Nerlov, Claus and Pietras, Eric and Mesnieres, Marion and Maes, Christa and Kumanogoh, Atsushi and Worzfeld, Thomas and Kharchenko, Peter and Scadden, David and Scialdone, Antonio and Spencer, Joel and Silberstein, Lev, Myeloid-Biased HSC Require Semaphorin 4A From the Bone Marrow Niche for Self-Renewal Under Stress and Life-Long Persistence. Available at SSRN: https://ssrn.com/abstract=4016764 or http://dx.doi.org/10.2139/ssrn.4016764
This version of the paper has not been formally peer reviewed.
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