Dynamics of human hematopoietic stem and progenitor cell differentiation to the erythroid lineage

Abstract

•Development of red blood cells from hematopoietic stem cells is a complex, dynamic, and hierarchical process.•Multiple immunophenotypic strategies exist for analysis of hematopoietic stem and progenitor cells (HSPCs) and erythroid cells.•Flow cytometry and single-cell RNA-sequencing studies have indicated heterogeneity within populations.•HSPCs exhibit a continuum of lineage priming, producing unipotent progenitors.•Systematic analysis is required to establish a standard set of erythroid markers. Erythropoiesis, the development of erythrocytes from hematopoietic stem cells, occurs through four phases: erythroid progenitor (EP) development, early erythropoiesis, terminal erythroid differentiation (TED), and maturation. According to the classical model that is based on immunophenotypic profiles of cell populations, each of these phases comprises multiple differentiation states that arise in a hierarchical manner. After segregation of lymphoid potential, erythroid priming begins during progenitor development and progresses through progenitor cell types that have multilineage potential. Complete separation of the erythroid lineage is achieved during early erythropoiesis with the formation of unipotent EPs: burst-forming unit-erythroid and colony-forming unit-erythroid. These erythroid-committed progenitors undergo TED and maturation, which involves expulsion of the nucleus and remodeling to form functional biconcave, hemoglobin-filled erythrocytes. In the last decade or so, many studies employing advanced techniques such as single-cell RNA-sequencing (scRNA-seq) as well as the conventional methods, including colony-forming cell assays and immunophenotyping, have revealed heterogeneity within the stem, progenitor, and erythroblast stages, and uncovered alternate paths for segregation of erythroid lineage potential. In this review, we provide an in-depth account of immunophenotypic profiles of all cell types within erythropoiesis, highlight studies that demonstrate heterogeneous erythroid stages, and describe deviations to the classical model of erythropoiesis. Overall, although scRNA-seq approaches have provided new insights, flow cytometry remains relevant and is the primary method for validation of novel immunophenotypes. Erythropoiesis, the development of erythrocytes from hematopoietic stem cells, occurs through four phases: erythroid progenitor (EP) development, early erythropoiesis, terminal erythroid differentiation (TED), and maturation. According to the classical model that is based on immunophenotypic profiles of cell populations, each of these phases comprises multiple differentiation states that arise in a hierarchical manner. After segregation of lymphoid potential, erythroid priming begins during progenitor development and progresses through progenitor cell types that have multilineage potential. Complete separation of the erythroid lineage is achieved during early erythropoiesis with the formation of unipotent EPs: burst-forming unit-erythroid and colony-forming unit-erythroid. These erythroid-committed progenitors undergo TED and maturation, which involves expulsion of the nucleus and remodeling to form functional biconcave, hemoglobin-filled erythrocytes. In the last decade or so, many studies employing advanced techniques such as single-cell RNA-sequencing (scRNA-seq) as well as the conventional methods, including colony-forming cell assays and immunophenotyping, have revealed heterogeneity within the stem, progenitor, and erythroblast stages, and uncovered alternate paths for segregation of erythroid lineage potential. In this review, we provide an in-depth account of immunophenotypic profiles of all cell types within erythropoiesis, highlight studies that demonstrate heterogeneous erythroid stages, and describe deviations to the classical model of erythropoiesis. Overall, although scRNA-seq approaches have provided new insights, flow cytometry remains relevant and is the primary method for validation of novel immunophenotypes. Mature human erythrocytes, or red blood cells (RBCs), are terminally differentiated biconcave disc-shaped cells that are 2.0–2.5 μm thick and 7 μm in diameter. RBCs lack a nucleus, as well as other intracellular organelles, and have a cytoplasm filled with hemoglobin (Hb) (∼250 million molecules per cell), which enables them to efficiently carry out their primary, integral function: transport of oxygen and carbon dioxide [1Corrons JLV Casafont LB Frasnedo EF. Concise review: how do red blood cells born, live, and die?.Ann Hematol. 2021; 100: 2425-2433Crossref PubMed Scopus (3) Google Scholar]. RBCs are the most abundant cell type in peripheral blood (PB), with a lifespan of 100–120 days in humans and maintenance of their levels requires daily production of ∼2 × 1011 cells (∼2 × 106 cells/second) [1Corrons JLV Casafont LB Frasnedo EF. Concise review: how do red blood cells born, live, and die?.Ann Hematol. 2021; 100: 2425-2433Crossref PubMed Scopus (3) Google Scholar,2Cosgrove J Hustin LSP de Boer RJ Perie L. Hematopoiesis in numbers.Trends Immunol. 2021; 42: 1100-1112Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Defects in RBC production result in anemia, which affects nearly one-third of the world's population and is associated with a wide variety of systemic pathologies ranging from vitamin deficiency to cancer [3Stevens GA Paciorek CJ Flores-Urrutia MC et al.National, regional, and global estimates of anaemia by severity in women and children for 2000-19: a pooled analysis of population-representative data.Lancet Glob Health. 2022; 10: e627-e639Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,4Chaparro CM Suchdev PS. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries.Ann N Y Acad Sci. 2019; 1450: 15-31PubMed Google Scholar]. Even mild anemia can be indicative of serious underlying diseases, including malignancy, HIV or other infections, renal insufficiency, and thalassemia. In adult humans, mature circulating RBCs are derived from hematopoietic stem cells (HSCs) in the bone marrow (BM) through the highly regulated process of erythropoiesis. The key driver of erythropoiesis is erythropoietin (EPO), an endogenous cytokine, which is produced by the kidneys and released in response to low PB oxygen [5Tsiftsoglou AS. Erythropoietin (EPO) as a key regulator of erythropoiesis, bone remodeling and endothelial transdifferentiation of multipotent mesenchymal stem cells (MSCs): implications in regenerative medicine.Cells. 2021; 10: 2140Crossref PubMed Scopus (16) Google Scholar,6Krantz SB Erythropoietin.Blood. 1991; 77: 419-434Crossref PubMed Google Scholar]. The classical model for erythropoiesis posits a hierarchical process that progresses through four phases: erythroid progenitor (EP) development, early erythropoiesis, terminal erythroid differentiation (TED), and erythrocyte maturation (Figure 1) [7Dzierzak E Philipsen S. Erythropoiesis: development and differentiation.Cold Spring Harb Perspect Med. 2013; 3a011601Crossref PubMed Scopus (197) Google Scholar, 8An X Mohandas N. Erythroblastic islands, terminal erythroid differentiation and reticulocyte maturation.Int J Hematol. 2011; 93: 139-143Crossref PubMed Scopus (45) Google Scholar, 9Hattangadi SM Wong P Zhang L Flygare J Lodish HF. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications.Blood. 2011; 118: 6258-6268Crossref PubMed Scopus (319) Google Scholar]. Early in hematopoiesis, HSCs form multipotent progenitors (MPPs), which in turn give rise to common lymphoid progenitors (CLPs) or common myeloid progenitors (CMPs) (Figure 1A) [10Kondo M Weissman IL Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow.Cell. 1997; 91: 661-672Abstract Full Text Full Text PDF PubMed Scopus (1673) Google Scholar,11Manz MG Miyamoto T Akashi K Weissman IL. Prospective isolation of human clonogenic common myeloid progenitors.Proc Natl Acad Sci USA. 2002; 99: 11872-11877Crossref PubMed Scopus (400) Google Scholar]. CLPs are committed to the lymphoid lineages including T, B, and natural killer cells, are committed to give rise to progenitors and progenitors early erythropoiesis, the unipotent progenitor cell burst-forming unit-erythroid by colony-forming unit-erythroid (Figure of to the the of TED and is by the of the erythroid lineage After are and the of erythropoiesis, is by expulsion of the nucleus from to of and other organelles, with biconcave disc-shaped RBCs P M Lodish HF. of chromatin and 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, M From to mature red blood in PubMed Scopus Google Scholar, J X Mohandas N remodeling during reticulocyte PubMed Scopus Google Scholar]. during development, and are from and myeloid cells are produced from progenitors and HSCs [7Dzierzak E Philipsen S. Erythropoiesis: development and differentiation.Cold Spring Harb Perspect Med. 2013; 3a011601Crossref PubMed Scopus (197) Google and erythropoiesis in PubMed Scopus Google Scholar, E hematopoietic stem cell and Full Text Full Text PDF PubMed Google Scholar, Zhang L P Zhang J The hematopoietic stem cell and in hematopoietic 2021; PubMed Scopus (3) Google Scholar, Hematopoiesis Spring Harb Perspect PubMed Scopus Google Scholar, in the to the of hematopoietic stem 2013; PubMed Scopus Google Scholar, J M of erythroid and myeloid progenitors in the and of the PubMed Google Scholar, L et hematopoietic stem erythropoiesis Med. 2021; PubMed Google Scholar]. erythropoiesis erythroid cells from cells in blood in the arise in the and the These progenitors erythrocytes to derived from HSCs in the to the of hematopoietic stem 2013; PubMed Scopus Google et of progenitors and underlying the PubMed Google Scholar]. In in the and in the erythropoiesis RBCs from the classical model erythropoiesis, and adult HSCs in their regenerative and differentiation HSCs erythroid lineage In erythroid cells from all have a cells and cells and with low levels of and adult RBCs and and low levels of and [7Dzierzak E Philipsen S. Erythropoiesis: development and differentiation.Cold Spring Harb Perspect Med. 2013; 3a011601Crossref PubMed Scopus (197) Google Zhang L P Zhang J The hematopoietic stem cell and in hematopoietic 2021; PubMed Scopus (3) Google of during development and erythroid Hematol. Full Text Full Text PDF PubMed Scopus Google Scholar]. In this review, we on erythroid development within the human describe the studies that to the development of profiles for cell types in the classical hierarchical model of human erythroid key progenitor, and erythroblast markers. highlight early that indicated deviations from the hierarchical model as well as heterogeneity in stem, progenitor, and erythroid we single-cell RNA-sequencing (scRNA-seq) studies that have the hierarchical model for erythropoiesis. These have revealed the of a stem and progenitor continuum lineage and to erythroid profiles of mouse HSCs and erythroid cells from of humans and have Hematopoiesis Spring Harb Perspect PubMed Scopus Google J Zhang J Y et analysis of terminal erythroid differentiation in novel method to and 2013; PubMed Scopus Google Scholar, CJ et of the and of a progenitor cell Full Text Full Text PDF PubMed Scopus Google Scholar, on hematopoietic stem cell PubMed Scopus Google Scholar, Y Identification and isolation of burst-forming and colony-forming erythroid progenitors from mouse by flow 2022; Scholar]. The classical or hierarchical model for erythropoiesis by immunophenotypic of or cell on by flow The differentiation states by cell and in colony-forming cell and analysis for and functional validation of multipotent cells, committed and [10Kondo M Weissman IL Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow.Cell. 1997; 91: 661-672Abstract Full Text Full Text PDF PubMed Scopus (1673) Google Scholar,11Manz MG Miyamoto T Akashi K Weissman IL. Prospective isolation of human clonogenic common myeloid progenitors.Proc Natl Acad Sci USA. 2002; 99: 11872-11877Crossref PubMed Scopus (400) Google J J et and functional of human at implications for of and erythropoiesis in 2013; PubMed Scopus Google Scholar, J J P et and of human erythroid and PubMed Scopus Google Scholar, Weissman IL. Identification of a of multipotent hematopoietic progenitors in human Full Text Full Text PDF PubMed Scopus Google Scholar, E of human hematopoietic stem cells of multilineage 2011; PubMed Scopus Google Scholar, L et of erythropoiesis in human bone of and J Hematol. 2021; PubMed Scopus Google Scholar, of of cells by erythropoietin in Natl Acad Sci USA. PubMed Google Scholar, K Miyamoto T Weissman IL clonogenic common myeloid progenitor that rise to all myeloid PubMed Scopus Google Scholar]. be we have to the of differentiation to for in this are in In and are as and and of hematopoietic types with myeloid cell T cell and T cell cell cell progenitor cell endothelial hematopoietic cells and type hematopoietic cells erythrocytes and and differentiation cells, T cells, the of cells, cells, cells, cells, early T cells, cells, endothelial cells, erythroid cells, endothelial endothelial cells, of cells, erythroid response to endothelial cell of progenitor cells, endothelial cell stem cell cells, for and hematopoietic progenitor cells, cells, endothelial cells, of cells, progenitor cell and early and endothelial for and and cell and hematopoietic and and blood cells, RBC to and in erythroid blood of erythrocyte blood lineage that as an and killer stem stem and progenitor stem in a new killer stem stem and progenitor stem development, progenitors with from HSCs (Figure the of immunophenotypic for human hematopoietic stem and progenitor cells (HSPCs) the as a by the on the of cells, and to be on a of human cells on mature lineage cells analysis of hematopoietic progenitor cell by a Immunol. PubMed Google and PubMed Google Scholar]. Early studies that cells in multipotent and a of and the to all blood lineages a that is to as and is the primary for CM Weissman IL of a human hematopoietic Natl Acad Sci USA. PubMed Google Scholar, of on human hematopoietic progenitor Med. PubMed Google Scholar, IL The of the and isolation of hematopoietic stem cells, and their to and PubMed Scopus Google Scholar, be a stem and Google Scholar]. of within the population that HSCs are a highly and human hematopoietic progenitor PubMed Google and myeloid differentiation of human stem PubMed Google Scholar]. analysis for of and that HSCs the and have in assays and Weissman IL. 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PubMed Google Scholar]. cells to have myeloid potential, cells erythroid et and of human hematopoietic cells from PubMed Scopus Google Scholar]. within the cells as and to give rise to erythroid and cells MG Miyamoto T Akashi K Weissman IL. Prospective isolation of human clonogenic common myeloid progenitors.Proc Natl Acad Sci USA. 2002; 99: 11872-11877Crossref PubMed Scopus (400) Google Scholar]. of to have potential, to give rise to and erythroid cells these and lymphoid potential. In immunophenotypic by or with of et K of the human progenitor the of and cells in early lymphoid Immunol. PubMed Scopus Google and as and from et L J and of human myeloid progenitor as common myeloid and Hematol. Full Text Full Text PDF PubMed Scopus Google and as as and as et J et human progenitors are in the PubMed Scopus Google that in the and and with other to their as that of be indicative of lineage by that cells have erythroid potential, cells have potential. Overall, a standard set of for immunophenotypic of is in the strategies by the Weissman are for isolation of populations, other strategies a set of MG Miyamoto T Akashi K Weissman IL. Prospective isolation of human clonogenic common myeloid progenitors.Proc Natl Acad Sci USA. 2002; 99: 11872-11877Crossref PubMed Scopus (400) Google Weissman IL. Identification of a of multipotent hematopoietic progenitors in human Full Text Full Text PDF PubMed Scopus Google Scholar]. although et Weissman IL. Identification of a of multipotent hematopoietic progenitors in human Full Text Full Text PDF PubMed Scopus Google and to and populations, et K of the human progenitor the of and cells in early lymphoid Immunol. 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PubMed Google CJ marrow cells of differentiation in of erythroid PubMed Google for production of in method for PubMed Google Scholar]. and are in and in are with of cells each and are with of cells each of the human hematopoietic progenitors and 1997; Google Scholar]. of the in in and during erythroblast development SB Erythropoietin.Blood. 1991; 77: 419-434Crossref PubMed Google SM Wong P Zhang L Flygare J Lodish HF. From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications.Blood. 2011; 118: 6258-6268Crossref PubMed Scopus (319) Google Scholar]. 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