Joji Fujisaki, MD, PhD
The stem cell niche, a specialized microenvironment where stem cells reside, has been extensively studied as a site that regulates stem cell fate or functions. However, immunological attributes of the stem cell niche have remained unexplored. Interestingly, the testis and the placenta, organs for residence of stem cells, were shown in the 1950s to be immunological sanctuaries, termed immune privileged (IP) sites, where stem cells are protected from immune attack. Potent endogenous immune suppressive mechanisms in IP sites enable persistence of transplanted allogeneic or xenogeneic grafts in the absence of immune suppressive therapy, distinguishing IP sites from other tissues. There is little information about whether tissue-committed stem cell niches are IP sites, similar to the testis and the placenta.
Our long-term goal is to test if stem cell niches are IP sites. Our recent study (published in Nature 2011) has demonstrated evidence indicating that, one of the best-characterized stem cell niches, the hematopoietic stem and progenitor cell (HSPC) niche in the bone marrow is an IP site. We demonstrated that the HSPC niche meets the experimental criterion of an IP site, a tissue where transplanted allogeneic (allo-) grafts can survive without immune suppression: we demonstrated surprisingly prolonged persistence of allo-HSPCs in immune competent mice without immune suppression. Moreover, using novel high-resolution in vivo microscopy that enables to visualize the location and the dynamic movement of individual cells in live mice, we demonstrated that FoxP3+ regulatory T cells (Tregs), a T cell subset with immune suppressive potential, preferentially form clusters with HSPCs. Treg depletion results in the loss of allo-HSPCs. The data indicate that Tregs play a critical role in maintaining IP of the HSPC niche that protects HSPCs from immunity.
Our current focus is to unveil the clinical significance of IP of the HSPC niche, especially to malignancies. More specifically, we will test whether the niche shields malignant stem cells that share properties with stem cells. We will further elucidate mechanisms allowing the niche to provide immune protection, using in vivo multiphoton/confocal microscopy to visualize the dynamic movement and interaction of immune cells in the niche in live mice.