| Popis: |
Stem cells reside in specialized regulatory microenvironments, termed niches, at several different locations within tissues1-3. The differential functions of heterogeneous stem cells and niches are important given increasing clinical application of stem cell transplantation and cancer immunotherapy. It remains unknown whether hierarchical arrangements amongst stem cells and distinct niches exist, and are responsible for aspects of immune tolerance. Here, we propose novel hierarchical arrangements within hematopoietic stem cells (HSCs) and bone marrow (BM) niches, that dictate both regenerative potential and immune privilege. High level nitric oxide-generating (NOHi) HSCs are refractory to immune attack; and exhibit “delayed” but robust long-term reconstitution. Such highly immune-privileged, primitive NOHi HSCs are present at distinct capillaries, characterized by primary cilia and high levels of the immune-checkpoint molecule CD200. These capillaries regulate regenerative functions of NOHi HSCs through cilia/CD200/eNOS/autophagy signals, further mediating immune-protection. Notably, described niche constituents, sinusoidal cells and Type H vessels2-10, co-localize with less immune-privileged and less potent NOLow HSCs. Therefore, we have identified highly immune-privileged, “late-rising” primitive HSCs and characterized immune-protective niches constituted of specialized vascular domains. Our studies suggest the niche may orchestrate stem cell hierarchy with immune tolerance, delineating future immunotherapeutic targets. |
