CD74 is a regulator of hematopoietic stem cell maintenance

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are a small population of undifferentiated cells that have the capacity for self-renewal and differentiate into all blood cell lineages. These cells are the most useful cells for clinical transplantations and for regenerative medicine. So far, it has not been possible to expand adult hematopoietic stem cells (HSCs) without losing their self-renewal properties. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF), and its mRNA is known to be expressed in HSCs. Here, we demonstrate that mice lacking CD74 exhibit an accumulation of HSCs in the bone marrow (BM) due to their increased potential to repopulate and compete for BM niches. Our results suggest that CD74 regulates the maintenance of the HSCs and CD18 expression. Its absence leads to induced survival of these cells and accumulation of quiescent and proliferating cells. Furthermore, in in vitro experiments, blocking of CD74 elevated the numbers of HSPCs. Thus, we suggest that blocking CD74 could lead to improved clinical insight into BM transplant protocols, enabling improved engraftment.

Hyaluronic acid–GPRC5C signalling promotes dormancy in haematopoietic stem cells

“…Similarly, we found enrichment of stem-cell-related genes (MEG3 and HIF1a) complemented by lower expression of activation-related genes (CDK6 and CD74 (ref. 23 ); Extended Data Fig. 2l ).…”

Single-Cell Transcriptome Analyses Reveal the Cell Diversity and Developmental Features of Human Gastric and Metaplastic Mucosa

“…As shown in Figure S2B, the LEFTY1+ cells also expressed CD44, another known stem cell marker (Ye et al, 2018). CCC analysis revealed that a signaling network of macrophage migration inhibitory factor (MIF), a ligand of the CD74+CD44 complex and CD74+CXCR4 complex (Becker-Herman et al, 2021; Shi et al, 2006), had characteristic features, i.e., many of MIF–(CD74+CD44) and MIF–(CD74+CXCR4) interactions are mediated by LEFTY1+ cells among all the cell types identified in gastric mucosa (Figure 7B). We conclude, therefore, that LEFTY1+ epithelial cells function as a hub of cellular communications via CD44 networks.…”

“…The multilayered interactions of LEFTY1+ cells with various other cells, including epithelial cell types, support our hypothesis that LEFTY1+ epithelial cells compose a possible stem cell cluster. CD74 is another communication partner of CD44, and the CD74–CD44 complex functions to prevent apoptosis and maintain stem cell properties (Becker-Herman et al, 2021; Gore et al, 2008; Shi et al, 2006). In contrast to other cell types, we found that a CD44 and CD74 coexpression pattern existed in LEFTY1+ epithelial cells (Figure S8B), providing further evidence that LEFTY1+ possible stem cells function in concert with the CD44 network.…”

Single-cell characterisation of the hematopoietic bone marrow interactome in health and disease

“…Loss of the interaction in AML was due to significant downregulation of CD74 expression, which occurred in 13 out of the 19 BM cell types. Loss of CD74 expression may contribute to enhanced fitness of leukemic HSC.MPPs, as CD74 has been reported to regulate HSPC maintenance and its deficiency in mice caused accumulation of HSPCs in the BM due to their increased potential to compete for BM niches [36].…”