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Myeloid Cell Origins, Differentiation, and Clinical Implications

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  • Authors: Kipp Weiskopf1, Peter J. Schnorr5, Wendy W. Pang8, Mark P. Chao12, Akanksha Chhabra15, Jun Seita16, Mingye Feng19, Irving L. Weissman22
  • Editor: Siamon Gordon25
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115; 2: Institute for Stem Cell Biology and Regenerative Medicine; 3: Ludwig Center for Cancer Stem Cell Research and Medicine; 4: Stanford Cancer Institute; 5: Institute for Stem Cell Biology and Regenerative Medicine; 6: Ludwig Center for Cancer Stem Cell Research and Medicine; 7: Stanford Cancer Institute; 8: Institute for Stem Cell Biology and Regenerative Medicine; 9: Ludwig Center for Cancer Stem Cell Research and Medicine; 10: Stanford Cancer Institute; 11: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; 12: Institute for Stem Cell Biology and Regenerative Medicine; 13: Ludwig Center for Cancer Stem Cell Research and Medicine; 14: Stanford Cancer Institute; 15: Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305; 16: Institute for Stem Cell Biology and Regenerative Medicine; 17: Ludwig Center for Cancer Stem Cell Research and Medicine; 18: Stanford Cancer Institute; 19: Institute for Stem Cell Biology and Regenerative Medicine; 20: Ludwig Center for Cancer Stem Cell Research and Medicine; 21: Stanford Cancer Institute; 22: Institute for Stem Cell Biology and Regenerative Medicine; 23: Ludwig Center for Cancer Stem Cell Research and Medicine; 24: Stanford Cancer Institute; 25: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
  • Received 02 April 2016 Accepted 08 September 2016 Published 21 October 2016
  • Kipp Weiskopf, kippw@alumni.stanford.edu; Irving L. Weissman, irv@stanford.edu
image of Myeloid Cell Origins, Differentiation, and Clinical Implications
  • Abstract:

    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. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types. The stages of hematopoiesis have been defined in both mice and humans. During embryological development, the earliest hematopoiesis takes place in yolk sac blood islands and then migrates to the fetal liver and hematopoietic organs. Some adult myeloid populations develop directly from yolk sac progenitors without apparent bone marrow intermediates, such as tissue-resident macrophages. Hematopoiesis also changes over time, with a bias of the dominating HSCs toward myeloid development as animals age. Defects in myelopoiesis contribute to many hematologic disorders, and some of these can be overcome with therapies that target the aberrant stage of development. Furthermore, insights into myeloid development have informed us of mechanisms of programmed cell removal. The CD47/SIRPα axis, a myeloid-specific immune checkpoint, limits macrophage removal of HSCs but can be exploited by hematologic and solid malignancies. Therapeutics targeting CD47 represent a new strategy for treating cancer. Overall, an understanding of hematopoiesis and myeloid cell development has implications for regenerative medicine, hematopoietic cell transplantation, malignancy, and many other diseases.

  • Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2016. Myeloid Cell Origins, Differentiation, and Clinical Implications. Microbiol Spectrum 4(5):MCHD-0031-2016. doi:10.1128/microbiolspec.MCHD-0031-2016.

Key Concept Ranking

Adaptive Immune System
0.829847
Innate Immune System
0.8020524
Immune Systems
0.56099916
Bone Marrow
0.5253239
Immune Cells
0.48243403
Acute Myeloid Leukemia
0.4307005
Mast Cells
0.42008013
Acute Promyelocytic Leukemia
0.41601753
0.829847
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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0031-2016
2016-10-21
2018-07-16

Abstract:

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. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types. The stages of hematopoiesis have been defined in both mice and humans. During embryological development, the earliest hematopoiesis takes place in yolk sac blood islands and then migrates to the fetal liver and hematopoietic organs. Some adult myeloid populations develop directly from yolk sac progenitors without apparent bone marrow intermediates, such as tissue-resident macrophages. Hematopoiesis also changes over time, with a bias of the dominating HSCs toward myeloid development as animals age. Defects in myelopoiesis contribute to many hematologic disorders, and some of these can be overcome with therapies that target the aberrant stage of development. Furthermore, insights into myeloid development have informed us of mechanisms of programmed cell removal. The CD47/SIRPα axis, a myeloid-specific immune checkpoint, limits macrophage removal of HSCs but can be exploited by hematologic and solid malignancies. Therapeutics targeting CD47 represent a new strategy for treating cancer. Overall, an understanding of hematopoiesis and myeloid cell development has implications for regenerative medicine, hematopoietic cell transplantation, malignancy, and many other diseases.

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Figures

Image of FIGURE 1
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 117 , with permission.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
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Image of FIGURE 2
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 10 , with permission.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
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Image of FIGURE 3
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 ( 46 ). 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.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
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Image of FIGURE 4
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 77 , with permission.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
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Image of FIGURE 5
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 92 , with permission.

Source: microbiolspec October 2016 vol. 4 no. 5 doi:10.1128/microbiolspec.MCHD-0031-2016
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