1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Myeloid Cell Origins, Differentiation, and Clinical Implications

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Buy this Microbiology Spectrum Article
Price Non-Member $15.00
  • 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
    Preview this microbiology spectrum article:
    Zoom in
    Zoomout

    Myeloid Cell Origins, Differentiation, and Clinical Implications, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/4/5/MCHD-0031-2016-1.gif /docserver/preview/fulltext/microbiolspec/4/5/MCHD-0031-2016-2.gif
  • 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

References

1. Ford CE, Hamerton JL, Barnes DW, Loutit JF. 1956. Cytological identification of radiation-chimaeras. Nature 177:452–454.[PubMed][CrossRef]
2. Till JE, McCulloch EA. 1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222. [PubMed][CrossRef]
3. Becker AJ, McCulloch EA, Till JE. 1963. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197:452–454. [PubMed][CrossRef]
4. Wu AM, Till JE, Siminovitch L, McCulloch EA. 1968. Cytological evidence for a relationship between normal hemotopoietic colony-forming cells and cells of the lymphoid system. J Exp Med 127:455–464. [PubMed][CrossRef]
5. Chen JY, Miyanishi M, Wang SK, Yamazaki S, Sinha R, Kao KS, Seita J, Sahoo D, Nakauchi H, Weissman IL. 2016. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530:223–227. [PubMed][CrossRef]
6. Adolfsson J, Borge OJ, Bryder D, Theilgaard-Mönch K, Astrand-Grundström I, Sitnicka E, Sasaki Y, Jacobsen SE. 2001. Upregulation of Flt3 expression within the bone marrow LinSca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15:659–669. [PubMed][CrossRef]
7. Christensen JL, Weissman IL. 2001. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A 98:14541–14546. [PubMed][CrossRef]
8. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–1121. [PubMed][CrossRef]
9. Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL. 1997. Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939. [PubMed]
10. Spangrude GJ, Heimfeld S, Weissman IL. 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241:58–62. [PubMed][CrossRef]
11. Smith LG, Weissman IL, Heimfeld S. 1991. Clonal analysis of hematopoietic stem-cell differentiation in vivo. Proc Natl Acad Sci U S A 88:2788–2792. [PubMed][CrossRef]
12. Ikuta K, Ingolia DE, Friedman J, Heimfeld S, Weissman IL. 1991. Mouse hematopoietic stem cells and the interaction of c-kit receptor and steel factor. Int J Cell Cloning 9:451–460. [PubMed][CrossRef]
13. Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. 2007. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 318:1296–1299. [PubMed][CrossRef]
14. Chhabra A, Ring AM, Weiskopf K, Schnorr PJ, Gordon S, Le AC, Kwon HS, Ring NG, Volkmer J, Ho PY, Tseng S, Weissman IL, Shizuru JA. 2016. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci Transl Med 8:351ra105. doi:10.1126/scitranslmed.aae0501. [PubMed][CrossRef]
15. Morrison SJ, Weissman IL. 1994. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1:661–673. [PubMed][CrossRef]
16. Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, Klein A, Hofmann O, Camargo FD. 2014. Clonal dynamics of native haematopoiesis. Nature 514:322–327. [PubMed][CrossRef]
17. Kondo M, Weissman IL, Akashi K. 1997. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661–672. [PubMed][CrossRef]
18. Akashi K, Traver D, Miyamoto T, Weissman IL. 2000. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404:193–197. [PubMed][CrossRef]
19. Warren L, Bryder D, Weissman IL, Quake SR. 2006. Transcription factor profiling in individual hematopoietic progenitors by digital RT-PCR. Proc Natl Acad Sci U S A 103:17807–17812. [PubMed][CrossRef]
20. Paul F, Arkin Y, Giladi A, Jaitin DA, Kenigsberg E, Keren-Shaul H, Winter D, Lara-Astiaso D, Gury M, Weiner A, David E, Cohen N, Lauridsen FK, Haas S, Schlitzer A, Mildner A, Ginhoux F, Jung S, Trumpp A, Porse BT, Tanay A, Amit I. 2015. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163:1663–1677. [PubMed][CrossRef]
21. Nakorn TN, Miyamoto T, Weissman IL. 2003. Characterization of mouse clonogenic megakaryocyte progenitors. Proc Natl Acad Sci U S A 100:205–210. [PubMed][CrossRef]
22. Terszowski G, Waskow C, Conradt P, Lenze D, Koenigsmann J, Carstanjen D, Horak I, Rodewald HR. 2005. Prospective isolation and global gene expression analysis of the erythrocyte colony-forming unit (CFU-E). Blood 105:1937–1945. [PubMed][CrossRef]
23. Iwasaki H, Mizuno S, Mayfield R, Shigematsu H, Arinobu Y, Seed B, Gurish MF, Takatsu K, Akashi K. 2005. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. J Exp Med 201:1891–1897. [PubMed][CrossRef]
24. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F. 2006. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311:83–87. [PubMed][CrossRef]
25. Traver D, Akashi K, Manz M, Merad M, Miyamoto T, Engleman EG, Weissman IL. 2000. Development of CD8α-positive dendritic cells from a common myeloid progenitor. Science 290:2152–2154. [PubMed][CrossRef]
26. Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ. 2005. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A 102:11408–11413. [PubMed][CrossRef]
27. Arinobu Y, Iwasaki H, Gurish MF, Mizuno S, Shigematsu H, Ozawa H, Tenen DG, Austen KF, Akashi K. 2005. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci U S A 102:18105–18110. [PubMed][CrossRef]
28. Murakami JL, Xu B, Franco CB, Hu X, Galli SJ, Weissman IL, Chen CC. 2016. Evidence that β7 integrin regulates hematopoietic stem cell homing and engraftment through interaction with MAdCAM-1. Stem Cells Dev 25:18–26. [PubMed][CrossRef]
29. Pronk CJ, Rossi DJ, Månsson R, Attema JL, Norddahl GL, Chan CK, Sigvardsson M, Weissman IL, Bryder D. 2007. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1:428–442. [PubMed][CrossRef]
30. Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. 1992. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A 89:2804–2808. [PubMed][CrossRef]
31. Michallet M, Philip T, Philip I, Godinot H, Sebban C, Salles G, Thiebaut A, Biron P, Lopez F, Mazars P, Roubi N, Leemhuis T, Hanania E, Reading C, Fine G, Atkinson K, Juttner C, Coiffier B, Fière D, Archimbaud E. 2000. Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution. Exp Hematol 28:858–870. [PubMed][CrossRef]
32. Negrin RS, Atkinson K, Leemhuis T, Hanania E, Juttner C, Tierney K, Hu WW, Johnston LJ, Shizurn JA, Stockerl-Goldstein KE, Blume KG, Weissman IL, Bower S, Baynes R, Dansey R, Karanes C, Peters W, Klein J. 2000. Transplantation of highly purified CD34+Thy-1+ hematopoietic stem cells in patients with metastatic breast cancer. Biol Blood Marrow Transplant 6:262–271. [PubMed][CrossRef]
33. Muller AM, Kohrt HE, Cha S, Laport G, Klein J, Guardino AE, Johnston LJ, Stockerl-Goldstein KE, Hanania E, Juttner C, Blume KG, Negrin RS, Weissman IL, Shizuru JA. 2012. Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells. Biol Blood Marrow Transplant 18:125–133. [PubMed][CrossRef]
34. Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. 1997. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A 94:5320–5325. [PubMed][CrossRef]
35. Uchida N, Sutton RE, Friera AM, He D, Reitsma MJ, Chang WC, Veres G, Scollay R, Weissman IL. 1998. HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells. Proc Natl Acad Sci U S A 95:11939–11944. [CrossRef]
36. Majeti R, Park CY, Weissman IL. 2007. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1:635–645. [PubMed][CrossRef]
37. Galy A, Travis M, Cen D, Chen B. 1995. Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 3:459–473. [PubMed][CrossRef]
38. Manz MG, Miyamoto T, Akashi K, Weissman IL. 2002. Prospective isolation of human clonogenic common myeloid progenitors. Proc Natl Acad Sci U S A 99:11872–11877. [PubMed][CrossRef]
39. Edvardsson L, Dykes J, Olofsson T. 2006. Isolation and characterization of human myeloid progenitor populations—TpoR as discriminator between common myeloid and megakaryocyte/erythroid progenitors. Exp Hematol 34:599–609. [PubMed][CrossRef]
40. Bühring HJ, Simmons PJ, Pudney M, Müller R, Jarrossay D, van Agthoven A, Willheim M, Brugger W, Valent P, Kanz L. 1999. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors. Blood 94:2343–2356. [PubMed]
41. Bühring HJ, Seiffert M, Giesert C, Marxer A, Kanz L, Valent P, Sano K. 2001. The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3. Blood 97:3303–3305. [PubMed][CrossRef]
42. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. 1999. Demonstration that human mast cells arise from a progenitor cell population that is CD34+, c-kit+, and expresses aminopeptidase N (CD13). Blood 94:2333–2342. [PubMed]
43. Mori Y, Iwasaki H, Kohno K, Yoshimoto G, Kikushige Y, Okeda A, Uike N, Niiro H, Takenaka K, Nagafuji K, Miyamoto T, Harada M, Takatsu K, Akashi K. 2009. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. J Exp Med 206:183–193. [PubMed][CrossRef]
44. Mori Y, Chen JY, Pluvinage JV, Seita J, Weissman IL. 2015. Prospective isolation of human erythroid lineage-committed progenitors. Proc Natl Acad Sci U S A 112:9638–9643. [PubMed][CrossRef]
45. Li J, Hale J, Bhagia P, Xue F, Chen L, Jaffray J, Yan H, Lane J, Gallagher PG, Mohandas N, Liu J, An X. 2014. Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood 124:3636–3645. [PubMed][CrossRef]
46. Seita J, Sahoo D, Rossi DJ, Bhattacharya D, Serwold T, Inlay MA, Ehrlich LI, Fathman JW, Dill DL, Weissman IL. 2012. Gene Expression Commons: an open platform for absolute gene expression profiling. PLoS One 7:e40321. doi:10.1371/journal.pone.0040321. [CrossRef]
47. Moore MA, Metcalf D. 1970. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 18:279–296. [PubMed][CrossRef]
48. Weissman IL, Baird S, Gardner RL, Papaioannou VE, Raschke W. Normal and neoplastic maturation of T-lineage lymphocytes. Cold Spring Harb Symp Quant Biol 41:9–21. [PubMed][CrossRef]
49. Weissman I, Papaioannou V, Gardner R. 1978. Fetal hematopoietic origins of the adult hematolymphoid system. Differ Norm Neoplast Hematopoietic Cells 5:33–47.
50. Medvinsky A, Dzierzak E. 1996. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86:897–906. [PubMed][CrossRef]
51. Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. 1998. A common precursor for hematopoietic and endothelial cells. Development 125:725–732. [PubMed]
52. Adamo L, García-Cardeña G. 2012. The vascular origin of hematopoietic cells. Dev Biol 362:1–10. [PubMed][CrossRef]
53. Ueno H, Weissman IL. 2006. Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev Cell 11:519–533. [PubMed][CrossRef]
54. Samokhvalov IM, Samokhvalova NI, Nishikawa S. 2007. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446:1056–1061. [PubMed][CrossRef]
55. Lux CT, Yoshimoto M, McGrath K, Conway SJ, Palis J, Yoder MC. 2008. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 111:3435–3438. [PubMed][CrossRef]
56. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. [PubMed][CrossRef]
57. Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, Leboeuf M, Low D, Oller G, Almeida F, Choy SH, Grisotto M, Renia L, Conway SJ, Stanley ER, Chan JK, Ng LG, Samokhvalov IM, Merad M, Ginhoux F. 2012. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209:1167–1181. [PubMed][CrossRef]
58. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. 2015. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551. [PubMed][CrossRef]
59. Sudo K, Ema H, Morita Y, Nakauchi H. 2000. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192:1273–1280. [PubMed][CrossRef]
60. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL. 2005. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102:9194–9199. [PubMed][CrossRef]
61. Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL. 2011. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A 108:20012–20017. [PubMed][CrossRef]
62. Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, Rossi DJ. 2010. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107:5465–5470. [PubMed][CrossRef]
63. Challen GA, Boles NC, Chambers SM, Goodell MA. 2010. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6:265–278. [PubMed][CrossRef]
64. Benz C, Copley MR, Kent DG, Wohrer S, Cortes A, Aghaeepour N, Ma E, Mader H, Rowe K, Day C, Treloar D, Brinkman RR, Eaves CJ. 2012. Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10:273–283. [PubMed][CrossRef]
65. Geiger H, de Haan G, Florian MC. 2013. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13:376–389. [PubMed][CrossRef]
66. Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. 2007. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5:e201. doi:10.1371/journal.pbio.0050201. [PubMed]
67. Beerman I, Rossi DJ. 2014. Epigenetic regulation of hematopoietic stem cell aging. Exp Cell Res 329:192–199. [PubMed][CrossRef]
68. Ergen AV, Boles NC, Goodell MA. 2012. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119:2500–2509. [PubMed][CrossRef]
69. Florian MC, Dörr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, Filippi MD, Hasenberg A, Gunzer M, Scharffetter-Kochanek K, Zheng Y, Geiger H. 2012. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10:520–530. [PubMed][CrossRef]
70. Weissman IL. 1996. From thymic lineages back to hematopoietic stem cells, sometimes using homing receptors. J Immunol 156:2019–2025. [PubMed]
71. Gambacorti-Passerini C, le Coutre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D, Pogliani E, Lydon NB. 1997. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 23:380–394. [PubMed][CrossRef]
72. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. 2004. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–667. [PubMed][CrossRef]
73. Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, Newton IG, Giles FJ, Durocher J, Creusot RS, Karimi M, Jones C, Zehnder JL, Keating A, Negrin RS, Weissman IL, Jamieson CH. 2009. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A 106:3925–3929. [PubMed][CrossRef]
74. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. 2007. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7:345–356. [PubMed][CrossRef]
75. Hantschel O, Grebien F, Superti-Furga G. 2012. The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL. Cancer Res 72:4890–4895. [PubMed][CrossRef]
76. Warrell RP Jr, de Thé H, Wang ZY, Degos L. 1993. Acute promyelocytic leukemia. N Engl J Med 329:177–189. [PubMed][CrossRef]
77. Pang WW, Pluvinage JV, Price EA, Sridhar K, Arber DA, Greenberg PL, Schrier SL, Park CY, Weissman IL. 2013. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci U S A 110:3011–3016. [PubMed][CrossRef]
78. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG. 2005. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397. [PubMed][CrossRef]
79. Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M, Jones C, Zehnder JL, Lilleberg SL, Weissman IL. 2006. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci U S A 103:6224–6229. [PubMed][CrossRef]
80. Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, Gattoni E, Pieri L, Guglielmelli P, Elena C, He S, Contel N, Mookerjee B, Sandor V, Cazzola M, Kantarjian HM, Barbui T, Vannucchi AM. 2014. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 120:513–520. [PubMed][CrossRef]
81. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S. 2015. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372:426–435. [PubMed][CrossRef]
82. Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. 2000. Role of CD47 as a marker of self on red blood cells. Science 288:2051–2054. [PubMed][CrossRef]
83. Adams S, van der Laan LJ, Vernon-Wilson E, Renardel de Lavalette C, Döpp EA, Dijkstra CD, Simmons DL, van den Berg TK. 1998. Signal-regulatory protein is selectively expressed by myeloid and neuronal cells. J Immunol 161:1853–1859. [PubMed]
84. Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, Bühring HJ. 1999. Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. Blood 94:3633–3643. [PubMed]
85. Seiffert M, Brossart P, Cant C, Cella M, Colonna M, Brugger W, Kanz L, Ullrich A, Bühring HJ. 2001. Signal-regulatory protein α (SIRPα) but not SIRPβ is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34+CD38 hematopoietic cells. Blood 97:2741–2749. [PubMed][CrossRef]
86. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, van Elsas A, Kuijpers TW, Bertucci F, van den Berg TK. 2011. CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A 108:18342–18347. [PubMed][CrossRef]
87. Ho CC, Guo N, Sockolosky JT, Ring AM, Weiskopf K, Özkan E, Mori Y, Weissman IL, Garcia KC. 2015. “Velcro” engineering of high affinity CD47 ectodomain as signal regulatory protein α (SIRPα) antagonists that enhance antibody-dependent cellular phagocytosis. J Biol Chem 290:12650–12663. [PubMed][CrossRef]
88. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, Traver D, van Rooijen N, Weissman IL. 2009. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138:271–285. [PubMed][CrossRef]
89. Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS. 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 8:1313–1323. [PubMed][CrossRef]
90. Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, Iwamoto C, Nishihara M, Iwasaki H, Miyamoto T, Honma N, Nakao M, Matozaki T, Akashi K. 2013. Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood 121:1316–1325. [PubMed][CrossRef]
91. Kuriyama T, Takenaka K, Kohno K, Yamauchi T, Daitoku S, Yoshimoto G, Kikushige Y, Kishimoto J, Abe Y, Harada N, Miyamoto T, Iwasaki H, Teshima T, Akashi K. 2012. Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis. Blood 120:4058–4067. [PubMed][CrossRef]
92. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, van Rooijen N, Weissman IL. 2009. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138:286–299. [PubMed][CrossRef]
93. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. 2015. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One 10:e0137345. doi:10.1371/journal.pone.0137345. [CrossRef]
94. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109:6662–6667. [PubMed][CrossRef]
95. Zhao H, Wang J, Kong X, Li E, Liu Y, Du X, Kang Z, Tang Y, Kuang Y, Yang Z, Zhou Y, Wang Q. 2016. CD47 promotes tumor invasion and metastasis in non-small cell lung cancer. Sci Rep 6:29719. doi:10.1038/srep29719. [PubMed][CrossRef]
96. Edris B, Weiskopf K, Volkmer AK, Volkmer JP, Willingham SB, Contreras-Trujillo H, Liu J, Majeti R, West RB, Fletcher JA, Beck AH, Weissman IL, van de Rijn M. 2012. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A 109:6656–6661. [PubMed][CrossRef]
97. Krampitz GW, George BM, Willingham SB, Volkmer JP, Weiskopf K, Jahchan N, Newman AM, Sahoo D, Zemek AJ, Yanovsky RL, Nguyen JK, Schnorr PJ, Mazur PK, Sage J, Longacre TA, Visser BC, Poultsides GA, Norton JA, Weissman IL. 2016. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A 113:4464–4469. [PubMed][CrossRef]
98. Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, Volkmer AK, Volkmer JP, Liu J, Lim JS, Yang D, Seitz G, Nguyen T, Wu D, Jude K, Guerston H, Barkal A, Trapani F, George J, Poirier JT, Gardner EE, Miles LA, de Stanchina E, Lofgren SM, Vogel H, Winslow MM, Dive C, Thomas RK, Rudin CM, van de Rijn M, Majeti R, Garcia KC, Weissman IL, Sage J. 2016. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 126:2610–2620. [PubMed][CrossRef]
99. Ngo M, Han A, Lakatos A, Sahoo D, Hachey SJ, Weiskopf K, Beck AH, Weissman IL, Boiko AD. 2016. Antibody therapy targeting CD47 and CD271 effectively suppresses melanoma metastasis in patient-derived xenografts. Cell Rep 16:1701–1716. [PubMed][CrossRef]
100. Liu X, Pu Y, Cron K, Deng L, Kline J, Frazier WA, Xu H, Peng H, Fu YX, Xu MM. 2015. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21:1209–1215. [PubMed][CrossRef]
101. Weiskopf K, Weissman IL. 2015. Macrophages are critical effectors of antibody therapies for cancer. MAbs 7:303–310. [PubMed][CrossRef]
102. Oldenborg PA, Gresham HD, Lindberg FP. 2001. CD47-signal regulatory protein α (SIRPα) regulates Fcγ and complement receptor-mediated phagocytosis. J Exp Med 193:855–862. [PubMed][CrossRef]
103. Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC. 2013. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341:88–91. [PubMed][CrossRef]
104. Weiskopf K, Ring AM, Schnorr PJ, Volkmer JP, Volkmer AK, Weissman IL, Garcia KC. 2013. Improving macrophage responses to therapeutic antibodies by molecular engineering of SIRPα variants. OncoImmunology 2:e25773. doi:10.4161/onci.25773. [CrossRef]
105. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R. 2010. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142:699–713. [PubMed][CrossRef]
106. Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL. 2013. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110:11103–11108. [PubMed][CrossRef]
107. Barclay AN, Van den Berg TK. 2014. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32:25–50. [PubMed][CrossRef]
108. Soto-Pantoja DR, Kaur S, Roberts DD. 2015. CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol 50:212–230. [PubMed][CrossRef]
109. Mateo V, Brown EJ, Biron G, Rubio M, Fischer A, Deist FL, Sarfati M. 2002. Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization. Blood 100:2882–2890. [PubMed][CrossRef]
110. Kikuchi Y, Uno S, Kinoshita Y, Yoshimura Y, Iida S, Wakahara Y, Tsuchiya M, Yamada-Okabe H, Fukushima N. 2005. Apoptosis inducing bivalent single-chain antibody fragments against CD47 showed antitumor potency for multiple myeloma. Leuk Res 29:445–450. [PubMed][CrossRef]
111. Manna PP, Frazier WA. 2004. CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res 64:1026–1036. [PubMed][CrossRef]
112. Reinhold MI, Lindberg FP, Kersh GJ, Allen PM, Brown EJ. 1997. Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J Exp Med 185:1–11. [PubMed][CrossRef]
113. Soto-Pantoja DR, Terabe M, Ghosh A, Ridnour LA, DeGraff WG, Wink DA, Berzofsky JA, Roberts DD. 2014. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res 74:6771–6783. [PubMed][CrossRef]
114. Lagasse E, Weissman IL. 1994. bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J Exp Med 179:1047–1052. [PubMed][CrossRef]
115. Feng M, Chen JY, Weissman-Tsukamoto R, Volkmer JP, Ho PY, McKenna KM, Cheshier S, Zhang M, Guo N, Gip P, Mitra SS, Weissman IL. 2015. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci U S A 112:2145–2150. [PubMed][CrossRef]
116. Chao MP, Jaiswal S, Weissman-Tsukamoto R, Alizadeh AA, Gentles AJ, Volkmer J, Weiskopf K, Willingham SB, Raveh T, Park CY, Majeti R, Weissman IL. 2010. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2:63ra94. doi:10.1126/scitranslmed.3001375. [CrossRef]
117. Seita J, Weissman IL. 2010. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2:640–653. [PubMed][CrossRef]
microbiolspec.MCHD-0031-2016.citations
cm/4/5
content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0031-2016
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0031-2016
2016-10-21
2017-12-12

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.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint
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
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error