Hematopoietic Stem Cell Niches and Signals Controlling Immune Cell Development and Maintenance of Immunological Memory

Abstract

Studies over the last couple of decades have shown that hematopoietic stem cells (HSCs) are critically dependent on cytokines such as Stem Cell Factor and other signals provided by bone marrow niches comprising of mesenchymal stem and progenitor cells (MSPCs) and endothelial cells (ECs). Because of their critical roles in HSC maintenance the niches formed by MSPCs and ECs are commonly referred to as HSC niches. For the most part, the signals required for HSC maintenance act in a short-range manner, which imposes the necessity for directional and positional cues in order for HSCs to localize and be retained properly in stem cell niches. The chemokine CXCL12 and its Gαi protein coupled receptor CXCR4, besides promoting HSC quiescence directly, also play instrumental roles in enabling HSCs to access bone marrow stem cell niches. Recent studies have revealed, however, that HSC niches also provide a constellation of hematopoietic cytokines that are critical for the production of most, if not all, blood cell types. Some hematopoietic cytokines, namely IL-7 and IL-15 produced by HSC niches, are not only required for lymphopoiesis but are also essential for memory T cell maintenance. Consequently, hematopoietic progenitors and differentiated immune cells, such as memory T cell subsets, also depend on the CXCL12/CXCR4 axis for migration into bone marrow and interactions with MSPCs and ECs. Similarly, subsets of antibody-secreting plasma cells also reside in close association with CXCL12-producing MSPCs in the bone marrow and require the CXCR4/CXCL12 axis for survival and long-term maintenance. Collectively, these studies demonstrate a broad range of key physiological roles, spanning blood cell production and maintenance of immunological memory, that are orchestrated by stem cell niches through a common and simple mechanism: CXCL12/CXCR4-mediated cell recruitment followed by receipt of a maintenance and/or instructive signal. A fundamental flaw of this type of cellular organization is revealed by myeloid and lymphoid leukemias, which target stem cell niches and induce profound transcriptomic changes that result in reduced hematopoietic activity and altered mesenchymal cell differentiation.

Hematopoietic Multipotent Progenitors and Plasma Cells: Neighbors or Roommates in the Mouse Bone Marrow Ecosystem?

“…These "MSCs" likely represent heterogeneous stromal subsets rather than bona fide mesenchymal stem cells (101,(122)(123)(124). As mentioned before, all stromal cells may not secrete CXCL12, and PSS cells (sometimes referred to as CXCL12-abundant reticular cells) are one of the main sources of this chemokine in the BM (17,57,65,125). Accordingly, BM PCs were reported to be in close contact with perivascular CXCL12+ stromal cells (57,126,127), but further characterization of this presumed dialogue is still lacking.…”

“…Several niche factors have been reported to provide HSCs with instructive clues to regulate their location, retention, self-renewing, and fate (57,(61)(62)(63)(64)(65). In particular, Stem Cell Factor (SCF) and CXCL12 are required for HSC maintenance and retention in the BM (17,63,66,67). PSS cells identified by surface expression of the Leptin receptor (LepR) promote HSC maintenance and the use of knock-in mouse models showed that these cells are the main source of SCF and CXCL12 (31,57,62,63,(67)(68)(69).…”

“…Therefore, MPPs share with HSCs the requirement for CXCL12 signaling and may reside in similar niches, but in closer association with IL-7+ cells. Indeed, depletion of CXCL12 or SCF expression from IL-7+ cells reduced both HSC and MPP numbers in the BM (17,69). Further insights into the role of the CXCR4/CXCL12 signaling axis on HSPC lineage commitment come from the study of a rare immunodeficiency called the WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome (14,(75)(76)(77), that leads to severe chronic panleukopenia.…”

“…Although not fully understood, it is now well established that BM environmental cues are integrated by hematopoietic cells throughout their differentiation and translate into distinct cell fates. As a typical example, the chemokine CXCL12 produced by non-hematopoietic stromal cells is essential to promote Common Lymphoid Progenitor (CLP) differentiation toward the B-cell lineage (15), through the progressive differentiation of pro-B cells into pre-B cells and then into immature B cells (16,17). This process is essential for efficient rearrangement of the immunoglobulin loci and production of a functional B-cell receptor (BCR) (18)(19)(20)(21).…”

“…Of note, most of these findings were made using mouse models and extracaution is required when extrapolating these data to human in which the BM composition might be different (e.g., the human BM contains noticeably more adipocytes). Because the roles of several cell types and many soluble and surface-anchored factors in the BM have been broadly studied and reviewed recently (17,(43)(44)(45)(46)(47)(48), we will focus on how the different BM niches can regulate and potentially determine HSC fate and differentiation into lineage-biased MPPs in mice. Moreover, we will discuss whether these early progenitors may share some niche elements with differentiated mature cells, namely PCs.…”