Chapter 50 : Myeloid Cell Origins, Differentiation, and Clinical Implications

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The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the blood and immune system. As the quintessential stem cell, it has the ability to self-replicate and differentiate into progeny of multiple lineages. Hematopoiesis describes the process of differentiating from HSCs to mature, functional cell types of the blood lineages. The existence of HSCs was first hypothesized following early experiments that demonstrated that animals receiving lethal doses of irradiation could be rescued by transplanting unfractionated bone marrow cells ( ). The transplanted cells repopulated the bone marrow of the recipients and gave rise to all the cells of the blood. In accordance with this observation, in 1961 Till and McCulloch showed that unfractionated bone marrow cells were able to generate mixed hematopoietic (myeloid and erythroid) colonies in the spleens of lethally irradiated mice ( ). They subsequently demonstrated that these colonies were formed by single cells that were capable of multilineage differentiation ( ). Given the limitations in technology at the time, they were unable to purify these cells further, and the experiment that showed clonal origin of spleen colonies did not include lymphoid cells ( ), although a later experiment did ( ). Years later, with the advent of monoclonal antibodies and fluorescence-activated cell sorting, these cells could be further characterized, purified, and evaluated in functional assays. Studies have now conclusively demonstrated that HSCs are a rare population of cells that give rise to all of the cells comprising the two main branches of the hematopoietic lineage: the myeloid arm and the lymphoid arm. In mice, all long-term HSCs (LT-HSCs) are Hoxb5 ( ) and located in the central marrow attached to the abluminal side of venous sinusoids.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 1

General organization of the hematopoietic lineage in mice and humans. The HSC can give rise to all of the cells of the blood and immune system, with multiple stepwise intermediates arising before developing into fully differentiated cells. The CMP and the CLP give rise to the two mains arms of the hematopoietic hierarchy. The CMP can give rise to all myeloid cells. Conventional surface markers for purifying each population are indicated for both mice and humans. GP, granulocyte progenitor; MacP, macrophage progenitor. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 2

Purification of the first HSCs. (A) Representative examples of purified HSCs as visualized by microscopy after hematoxylin staining. (B) Myeloerythroid colonies in the spleen formed by the injection of purified HSCs into lethally irradiated mice. (C) A single lymphoid colony in the thymus formed by the injection of purified HSCs into lethally irradiated mice. (D) Fluorescence-activated cell sorting depicting HSCs as Thy-1Sca-1. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 3

RNA expression pattern of IL-7Rα throughout the murine hematopoietic lineage. IL-7Rα is a critical surface molecule that helps distinguish the lymphoid arm of the hematopoietic system from HSCs, progenitors, and myeloid cells. Each box represents a different hematopoietic subpopulation. Blue indicates lower expression; pink indicates higher expression. Analysis performed using Gene Expression Commons ( ). BM, bone marrow; Spl, spleen; GMLP, granulocyte/macrophage/lymphoid progenitor subset; p, pre-; s, strict; Plt, platelet; Ery, erythrocyte; Gra, granulocyte; Mono, monocyte; BLP, earliest B-lymphoid progenitor; Fr, B cell subset fraction; T1B, T1 B cell; T2B, T2 B cell; MzB, marginal zone B cell; FoB, follicular B cell; iNK, intermediate NK cell; DN, double negative T cell subset; DP, double positive T cell subset. CD4 and CD8 populations represent mature T cells.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 4

GMP frequency is decreased in low-risk MDS. Representative example of how hematopoietic progenitor cell populations can be altered in states of disease. (A) Frequency of GMPs out of total myeloid progenitors in normal, low-risk MDS and non-MDS diseased bone marrow samples. (B) Frequency of GMPs out of total lineage-negative bone marrow mononuclear cells in normal and low-risk MDS bone marrow samples. Asterisks indicate statistically significant differences: * < 10–13, ** < 10–10, *** < 0.0006. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 5

CD47-blocking therapies are effective in preclinical models of human cancer. Xenograft studies of mice engrafted with human AML samples that were then treated with anti-CD47 antibodies. (A) Anti-CD47 antibody treatment decreases leukemia burden, as assessed by the percent of human chimerism in the bone marrow (BM) after 14 days of treatment. (B) Bone marrow histology showing leukemia infiltration in control mice (top left, bottom left), and eradication of disease in mice treated with anti-CD47 antibodies (top middle, bottom middle). In some mice with residual tumor burden following treatment with anti-CD47 antibodies (top right, bottom right), macrophages could be seen in the bone marrow engulfing leukemia cells (black arrows). Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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