In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche

Abstract

Stem cells reside in a specialized regulatory microenvironment or niche1,2, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity1-3. The niche may also protect stem cells from environmental insults3 including cytotoxic chemotherapy and perhaps pathogenic immunity4. The testis, hair follicle, and placenta are all sites of residence for stem cells and are immune suppressive environments, called immune privileged (IP) sites, where multiple mechanisms conspire to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression (IS)4. We sought to determine if somatic stem cell niches more broadly are IP sites by examining the hematopoietic stem/progenitor cell (HSPC) niche1,2,5-7 in the bone marrow (BM), a site where immune reactivity exists8,9. We observed persistence of allo-HSPCs in non-irradiated recipients for 30 days without IS with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T cells (Tregs). High resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with Tregs that accumulated on the endosteal surface in the calvarial and trabecular BM. Tregs appear to participate in creating a localized zone where HSPCs reside and where Tregs are necessary for allo-HSPC persistence. In addition to processes supporting stem cell function, the niche will provide a relative sanctuary from immune attack.

Quantification and three-dimensional microanatomical organization of the bone marrow

“…112 Regulatory T cells (T regs ) have been reported to lodge in close proximity to the endosteum of trabecular bone. 113 14 FEBRUARY 2017 x VOLUME 1, NUMBER Figure 2 and described in detail by Mercier et al 63 ). Many of the niches are constructed around diverse microvessel types, which distinctly regulate access to nutrients, oxygen, and metabolites derived from circulating blood.…”

Ex vivo expansion of hematopoietic stem cells

“…In addition, macrophages [42,43], megakaryocytes [44,45], the sympathetic nervous system [46], and adipocytes [47] have also been shown to play roles in the HSC niches. Furthermore, regulatory T cells co-localize with HSCs in the endosteal area of the bone marrow and protect HSCs from immune attack [48]. The clarification of the nature of HSC niche will facilitate to design better strategies for ex vivo expansion of HSCs.…”

Aging of the hematopoietic stem cells niche

“…The currently identified niche cells that are non-hematopoietic in origin include immature osteoblasts [8,9], endothelial cells [10,11], perivascular cells [10,12], mesenchymal stem cells (MSC) [13], sympathetic nerve cells [14], adipocytes [15], and non-myelinating Schwann cells [16]. Nonetheless, mature hematopoietic cells such as macrophages/monocytes [17] and regulatory T-cells [18], as well as osteoclasts [19], also regulate HSCs or progenitor cells, primarily in an indirect manner through modulation of non-hematopoietic niche cells. Collectively, niche cells regulate HSCs through the production of an array of cytokines, such as angiopoietin-1 (Ang-1), CXCL12, and thrombopoietin (TPO), and extracellular matrix proteins, such as osteopontin and tenascin-C, as well as adhesion molecules such as N-cadherin [10,12,[20][21][22][23][24] (Fig.…”