CD74 is a regulator of hematopoietic stem cell maintenance.

Shirly Becker-Herman,Hadas Lewinsky,Lihi Radomir,Lital Sever,Milena Rozenberg,Idit Shachar,Amnon Peled,Richard Bucala,Keren David,Avital Barak,Carmit Hillel-Karniel,Mattias P Kramer,Michal Levi,Naama Gil-Yarom,Gilgi Friedlander,Connie J Eaves

doi:10.1371/journal.pbio.3001121

Shirly Becker-Herman, Hadas Lewinsky + Show 14 more

Open Access

https://doi.org/10.1371/journal.pbio.3001121

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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.

Highlights

Host immunity requires a constant renewal of red blood cells and leukocytes throughout life, as these cells have a restricted life span
CD74 mRNA levels were analyzed in hematopoietic stem and progenitor cell (HSPC) (Lin-Sca-1+c-Kit+; LSK) [9,10,11], which are enriched for hematopoietic stem (CD34-Lin-Sca-1+c-Kit+; hematopoietic stem cell (HSC)) and progenitor (CD34 + Lin-Sca-1+c-Kit+; hematopoietic progenitor cell (HPC)) cells [10,23,24]
And 6K, higher numbers of both quiescent and cycling cells were detected in CD74−/− mice, no significant change in the ratio of these populations was observed. These results suggest that the HSC and HSPC compartments are larger in mice lacking CD74, there is no overproliferation of any specific population, and the proportion of proliferating cells is similar in the WT and CD74−/− mice

Summary

Introduction

Host immunity requires a constant renewal of red blood cells and leukocytes throughout life, as these cells have a restricted life span. Hematopoietic cell turnover is enhanced following acute stress situations, such as infections or irradiation, by the proliferation of hematopoietic stem cells (HSCs) and progenitor cells (HPCs), which respond to these conditions. HSCs are defined by their capacity for self-renewal and ability to differentiate into all blood cell lineages. Another distinct feature of these cells is their ability to migrate out of the BM to the peripheral blood. This process is enhanced under stress as a part of the host mechanisms of defense and repair.

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