Hematopoiesis: an evolving paradigm for stem cell biology

Abstract

Establishment and maintenance of the blood system relies on self-renewing hematopoietic stem cells (HSCs) that normally reside in small numbers in the bone marrow niche of adult mammals. This Review describes the developmental origins of HSCs and the molecular mechanisms that regulate lineage-specific differentiation. Studies of hematopoiesis provide critical insights of general relevance to other areas of stem cell biology including the role of cellular interactions in development and tissue homeostasis, lineage programming and reprogramming by transcription factors, and stage- and age-specific differences in cellular phenotypes.

Figure 1. Developmental Regulation of Hematopoiesis in the Mouse

(A) Hematopoiesis occurs first in the yolk sac (YS) blood islands and later at the aorta-gonad mesonephros (AGM) region, placenta, and fetal liver (FL). YS blood islands are visualized by LacZ staining of transgenic embryo expression GATA-1- driven LacZ. AGM and FL are stained by LacZ in Runx1-LacZ knockin mice. (Photos courtesy of Y. Fujiwara and T. North.). (B) Hematopoiesis in each location favors the production of specific blood lineages. Abbreviations: ECs, endothelial cells; RBCs, red blood cells; LTHSC, long-term hematopoietic stem cell; ST-HSC, short-term hematopoietic stem cell; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte/erythroid progenitor; GMP, granulocyte/macrophage progenitor. (C) Developmental timewindows for shifting sites of hematopoiesis.

Figure 2. Hematopoietic Development in the Zebrafish

(A) Hematopoiesis occurs first in the intermediate cell mass (ICM) and subsequently in the aorta-go-nad mesonephros (AGM) region and caudal hematopoietic tissue (CHT). Later hematopoietic cells are found in the kidney as well as in the thymus. In situ hybridization for GATA-1 at 30 hr (ICM), for c-myb at 36 hr (AGM), for SCL/tal1 at days 4 and 6.5 (CHT), and for c-myb at day 6 (top view) to demonstrate expression in the kidney marrow and thymus. (Photos courtesy of X. Bai and T. Bowman.) (B) Developmental time windows for hematopoietic sites in the zebrafish.

Figure 3. Stem Cell Niche in the Adult Bone Marrow

HSCs are found adjacent to osteoblasts that are under the regulation of bone morphogenetic protein (BMP) (the osteobast niche). HSCs are also found adjacent to blood vessels (the vascular niche). The chemokine CXCL12 regulates the migration of HSCs from the circulation to the bone marrow. The osteoblast and vascular niches in vivo lie in close proximity or may be interdigitated. The marrow space also contains stromal cells that support hematopoiesis including the production of cytokines, such as c-Kit ligand, that stimulate stem cells and progenitors. Cytokines, including interleukins, thrombopoietin (Tpo), and erythropoietin (Epo), also influence progenitor function and survival.

Figure 4. Requirements of Transcription Factors in Hematopoiesis

The stages at which hematopoietic development is blocked in the absence of a given transcription factor, as determined through conventional gene knockouts, are indicated by red bars. The factors depicted in black have been associated with oncogenesis. Those factors in light font have not yet been found translocated or mutated in human/mouse hematologic malignancies. Abbreviations: LT-HSC, long-term hematopoietic stem cell; ST-HSC, short-term hematopoietic stem cell; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte/erythroid progenitor; GMP, granulocyte/macrophage progenitor; RBCs, red blood cells.

Figure 5. Transcription Factor Antagonism in Lineage Determination

Examples of antagonism are depicted in red. The transcription factors present in the mature precursors following choice of specific lineage are shown at the bottom in black. Abbreviations: CMP, common myeloid progenitor; MEP, megakaryocyte/erythroid progenitor; GMP, granulocyte/macrophage progenitor; RBCs, red blood cells.

Figure 6. Reprogramming of Hematopoietic Lineages

The orange arrows depict lineage reprogramming upon expression of the transcription factors GATA-1, C/EBP, or GATA-3. Abbreviations: HSC, hematopoietic stem cell; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte/erythroid progenitor; GMP, granulocyte/ macrophage progenitor.