Vade-MECOM: How to peel back the layers of hematopoiesis

A recent study1Yokomizo T. Ideue T. Morino-Koga S. Tham C.Y. Sato T. Takeda N. Kubota Y. Kurokawa M. Komatsu N. Ogawa M. et al.Independent origins of fetal liver haematopoietic stem and progenitor cells.Nature. 2022; : 1-6https://doi.org/10.1038/s41586-022-05203-0Crossref Scopus (24) Google Scholar demonstrates how hematopoietic stem cells (HSCs) contribute minimally to blood and immune cell production during development and only become active postnatally. The work also reveals how Mecom expression can be used to distinguish rare HSCs from the more abundant progenitors that arise to maintain embryonic hematopoiesis. A recent study1Yokomizo T. Ideue T. Morino-Koga S. Tham C.Y. Sato T. Takeda N. Kubota Y. Kurokawa M. Komatsu N. Ogawa M. et al.Independent origins of fetal liver haematopoietic stem and progenitor cells.Nature. 2022; : 1-6https://doi.org/10.1038/s41586-022-05203-0Crossref Scopus (24) Google Scholar demonstrates how hematopoietic stem cells (HSCs) contribute minimally to blood and immune cell production during development and only become active postnatally. The work also reveals how Mecom expression can be used to distinguish rare HSCs from the more abundant progenitors that arise to maintain embryonic hematopoiesis. The development of the mammalian embryo is a complex and highly regulated process that involves seemingly contradictory goals: enable robust expansion and differentiation of cells that allow for effective growth of the embryo, while also producing and preserving rare stem cell populations that must persist over the life of the organism. Perhaps this is most clearly illustrated by the formation of the blood and immune systems through hematopoiesis. These blood and immune cells need to expand in numbers by thousands-of-fold during development to keep pace with embryonic growth. They also produce the hematopoietic stem cell (HSC) population that drives hematopoiesis throughout life.2Pucella J.N. Upadhaya S. Reizis B. The Source and Dynamics of Adult Hematopoiesis: Insights from Lineage Tracing.Annu Rev Cell Dev Bi. 2020; 36: 1-22https://doi.org/10.1146/annurev-cellbio-020520-114601Crossref PubMed Scopus (23) Google Scholar It has long been appreciated that to allow for these contrasting goals, the hematopoietic system has a layered architecture. Distinct transient waves of blood and immune cell production initially arise from short-lived progenitors, derived from the yolk sac and other embryonic structures3Herzenberg L.A. Herzenberg L.A. Toward a layered immune system.Cell. 1989; 59: 953-954https://doi.org/10.1016/0092-8674(89)90748-4Abstract Full Text PDF PubMed Scopus (216) Google Scholar,4Dzierzak E. Bigas A. Blood Development: Hematopoietic Stem Cell Dependence and Independence.Cell Stem Cell. 2018; 22: 639-651https://doi.org/10.1016/j.stem.2018.04.015Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar (Figure 1). Only later, around embryonic day 11 in mice, HSCs are first detected in the aorta-gonad-mesonephros (AGM) region.5Medvinsky A. Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region.Cell. 1996; 86: 897-906Abstract Full Text Full Text PDF PubMed Scopus (1195) Google Scholar In this region, specialized endothelial cells of the dorsal aorta, termed hemogenic endothelial cells, transition to generate intra-aortic hematopoietic clusters. These clusters contain both HSCs and progenitors for the embryo. Presumably, both populations immediately begin contributing to developmental hematopoiesis, although this has not been thoroughly measured. Similarly, how the heterogeneity of HSCs and other progenitors derived from the AGM is established remains unknown. Yokomizo et al. have now addressed these long-standing mysteries.1Yokomizo T. Ideue T. Morino-Koga S. Tham C.Y. Sato T. Takeda N. Kubota Y. Kurokawa M. Komatsu N. Ogawa M. et al.Independent origins of fetal liver haematopoietic stem and progenitor cells.Nature. 2022; : 1-6https://doi.org/10.1038/s41586-022-05203-0Crossref Scopus (24) Google Scholar The authors designed a lineage-tracing approach using the transcription factor Hlf, which in the AGM is found in both HSCs and hematopoietic progenitors. They demonstrated almost simultaneous expansion of both progenitors and HSCs within the fetal liver. Marked cells then seemed to actively contribute to developmental hematopoiesis. This finding would be consistent with a layered, rather than hierarchical model of definitive hematopoiesis, even within the wave of hematopoiesis arising from the AGM. In examining gene expression differences between populations marked by Hlf that arise from the AGM, Yokomizo et al. found that expression of the transcription factor Mecom is restricted to the HSC population. Mecom, also referred to as the Mds1-Evi1 complex locus, is a known HSC regulator and was first identified as a site of proviral insertion in murine myeloid leukemias.6Mucenski M.L. Taylor B.A. Ihle J.N. Hartley J.W. Morse H.C. Jenkins N.A. Copeland N.G. Identification of a common ecotropic viral integration site, Evi-1, in the DNA of AKXD murine myeloid tumors.Mol. Cell Biol. 1988; 8: 301-308https://doi.org/10.1128/mcb.8.1.301-308.1988Crossref PubMed Google Scholar In humans, MECOM can be overexpressed via chromosomal rearrangements in acute myeloid leukemia.7Balgobind B.V. Lugthart S. Hollink I.H. Arentsen-Peters S.T.J.C.M. van Wering E.R. de Graaf S.S.N. Reinhardt D. Creutzig U. Kaspers G.J.L. de Bont E.S.J.M. et al.EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia.Leukemia. 2010; 24: 942-949https://doi.org/10.1038/leu.2010.47Crossref PubMed Scopus (64) Google Scholar On the other hand, its haploinsufficiency causes severe neonatal bone marrow failure.8Voit R.A. Tao L. Yu F. Cato L.D. Cohen B. Liao X. Fiorini C. Nandakumar S.K. Wahlster L. Teichert K. et al.A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.bioRxiv. 2022; (2021.12.09.471942)https://doi.org/10.1101/2021.12.09.471942Crossref Scopus (0) Google Scholar Hence, Mecom is an important regulator of HSC maintenance, but its precise role in the development of HSCs is unclear. By generating another lineage tracing approach through modification of the Mecom locus, the authors found that expression of the Mecom tracer is heterogeneous in Hlf-positive clusters in the AGM. They established Mecom as a key marker of cells fated to become HSCs. In addition, stem versus progenitor fate choices within the Hlf-positive AGM population could be altered via genetic manipulation of Mecom expression. Notably, Mecom+/− midgestation embryos displayed a markedly reduced HSC compartment. This result further underscores that Mecom levels are important for the establishment of a proper stemness program during hematopoietic development. It is in line with observations in some human neonates, where MECOM haploinsufficiency drives a bone marrow failure due to an almost complete absence of HSCs.8Voit R.A. Tao L. Yu F. Cato L.D. Cohen B. Liao X. Fiorini C. Nandakumar S.K. Wahlster L. Teichert K. et al.A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia.bioRxiv. 2022; (2021.12.09.471942)https://doi.org/10.1101/2021.12.09.471942Crossref Scopus (0) Google Scholar Remarkably, the tracing of Mecom high-expressing cells determined that fetal HSCs minimally contribute to blood cell production before birth, in line with several recent reports.9Soares-da-Silva F. Freyer L. Elsaid R. Burlen-Defranoux O. Iturri L. Sismeiro O. Pinto-do-Ó P. Gomez-Perdiguero E. Cumano A. Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life.J. Exp. Med. 2021; 218https://doi.org/10.1084/jem.20201729Crossref PubMed Google Scholar These very important findings represent an important step in our understanding of how the heterogeneity of the hematopoietic system is established. At the same time, they raise a number of interesting questions. First, what drives Mecom expression heterogeneity in the hematopoietic clusters of the AGM? It would be important to know whether Mecom high-expressing cells are located in distinct regions of the dorsal aorta. Such specific distribution would suggest the existence of different niches for HSCs and other progenitors in the AGM. In addition, further studies are needed to understand at what point the heterogeneity in Mecom arises in the hematopoietic clusters of the AGM. Future work might unveil the genetic programs differentially activated in cells of the AGM expressing different levels of Mecom and whether this heterogeneity results in progeny with different functions. Does higher expression of Mecom activate distinct genes? Elucidating the regulators of Mecom expression during embryonic development will guide efforts to efficiently differentiate human pluripotent stem cells (hPSCs) into HSCs. In fact, it is now possible to generate hPSC-derived hemogenic endothelial cells that are multipotent and capable of transient, but not long-term, reconstitution upon transplantation.10Luff S.A. Creamer J.P. Valsoni S. Dege C. Scarfò R. Dacunto A. Cascione S. Randolph L.N. Cavalca E. Merelli I. et al.Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells.Nat. Cell Biol. 2022; 1: 9https://doi.org/10.1038/s41556-022-00898-9Crossref Scopus (9) Google Scholar These cells are transcriptionally very similar to the HSC-generating cells found in the dorsal aorta of human embryos and express MECOM. However, it is plausible that these MECOM expression levels are insufficient for HSC specification and maintenance. Finally, the work of Yokomizo et al. adds another layer of complexity (no pun intended) to hematopoietic development. The paper provides an elegant explanation for how the embryo balances the rapid growth of blood and immune systems with preservation of the HSC supply for lifelong blood production. Further studies will enable us to peel back additional layers of hematopoiesis to understand how this intricate process is orchestrated. V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, and Cellarity, all unrelated to the present work.