BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

The maintenance mechanism of hematopoietic stem cell dormancy: role for a subset of macrophages

  • Cheong-Whan Chae (Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital) ;
  • Gun Choi (Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University) ;
  • You Ji Kim (Department of Medicine, Seoul National University College of Medicine) ;
  • Mingug Cho (Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University) ;
  • Yoo-Wook Kwon (Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital) ;
  • Hyo-Soo Kim (Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital)
  • Received : 2023.05.20
  • Accepted : 2023.08.11
  • Published : 2023.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we describe the role of KAI1, which is mainly expressed on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs), in niche-mediated LT-HSC maintenance. KAI1 activates TGF-β1/Smad3 signal in LT-HSCs, leading to the induction of CDK inhibitors and inhibition of the cell cycle. The KAI1-binding partner DARC is expressed on macrophages and stabilizes KAI1 on LT-HSCs, promoting their quiescence. Conversely, when DARC+ BM macrophages were absent, the level of surface KAI1 on LT-HSCs decreases, leading to cell-cycle entry, proliferation, and differentiation. Thus, KAI1 acts as a functional surface marker of LT-HSCs that regulates dormancy through interaction with DARC-expressing macrophages in the BM stem cell niche. Recently, we showed very special and rare macrophages expressing α-SMA+ COX2+ & DARC+ induce not only dormancy of LT-HSC through interaction of KAI1-DARC but also protect HSCs by down-regulating ROS through COX2 signaling. In the near future, the strategy to combine KAI1-positive LT-HSCs and α-SMA/Cox2/DARC triple-positive macrophages will improve the efficacy of stem cell transplantation after the ablative chemo-therapy for hematological disorders including leukemia.

Keywords

Acknowledgement

This work was supported by Technology R&D Project "Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer (HI17C2085)" and "Korea Research-Driven Hospital (HI14C1277)" through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea.

References

  1. Cheshier SH, Morrison SJ, Liao X and Weissman IL (1999) In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A 96, 3120-3125 https://doi.org/10.1073/pnas.96.6.3120
  2. Skulimowska I, Sosniak J, Gonka M, Szade A, Jozkowicz A and Szade K (2022) The biology of hematopoietic stem cells and its clinical implications. FEBS J 289, 7740-7759 https://doi.org/10.1111/febs.16192
  3. Kwon YW, Chae CW, Lee H et al (2022) A subset of macrophages and monocytes in the mouse bone marrow express atypical chemokine receptor 1. Cell Stem Cell 29, 1016-1017 https://doi.org/10.1016/j.stem.2022.06.011
  4. Hur J, Choi JI, Lee H et al (2016) CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages. Cell Stem Cell 18, 508-521 https://doi.org/10.1016/j.stem.2016.01.013
  5. Liu WM and Zhang XA (2006) CD82, a tumor metastasis suppressor. Cancer Lett 240, 183-194 https://doi.org/10.1016/j.canlet.2005.08.018
  6. Miranti CK (2009) Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. Cell Signal 21, 196-211 https://doi.org/10.1016/j.cellsig.2008.08.023
  7. Kim JH, Kim B, Cai L et al (2005) Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature 434, 921-926 https://doi.org/10.1038/nature03452
  8. Custer MC, Risinger JI, Hoover S, Simpson RM, Patterson T and Barrett JC (2006) Characterization of an antibody that can detect the Kai1/CD82 murine metastasis suppressor. Prostate 66, 567-577 https://doi.org/10.1002/pros.20386
  9. Hall A, Fontelonga T, Wright A et al (2020) Tetraspanin CD82 is necessary for muscle stem cell activation and supports dystrophic muscle function. Skelet Muscle 10, 34
  10. Engel P and Tedder TF (1994) New CD from the B cell section of the fifth international workshop on human leukocyte differentiation antigens. Leuk Lymphoma 13 Suppl 1, 61-64 https://doi.org/10.3109/10428199409052677
  11. Tsai YC and Weissman AM (2011) Dissecting the diverse functions of the metastasis suppressor CD82/KAI1. FEBS Lett 585, 3166-3173 https://doi.org/10.1016/j.febslet.2011.08.031
  12. Alexander MS, Rozkalne A, Colletta A et al (2016) CD82 is a marker for prospective isolation of human muscle satellite cells and is linked to muscular dystrophies. Cell Stem Cell 19, 800-807 https://doi.org/10.1016/j.stem.2016.08.006
  13. Dong JT, Lamb PW, Rinker-Schaeffer CW et al (1995) KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884-886 https://doi.org/10.1126/science.7754374
  14. Risinger JI, Custer M and Feigenbaum L (2014) Normal viability of Kai1/Cd82 deficient mice. Mol Carcinog 53, 610-624
  15. Bergsma A, Ganguly SS, Dick D, Williams BO and Miranti CK (2018) Global deletion of tetraspanin CD82 attenuates bone growth and enhances bone marrow adipogenesis. Bone 113, 105-113 https://doi.org/10.1016/j.bone.2018.05.020
  16. Saito-Reis CA, Balise VD, Pascetti EM, Jiminez M and Gillette JM (2021) Tetraspanin CD82 regulates S1PR(1)-mediated hematopoietic stem and progenitor cell mobilization. Stem Cell Reports 16, 2422-2431 https://doi.org/10.1016/j.stemcr.2021.08.009
  17. Bonavita O, Mollica Poeta V, Setten E, Massara M and Bonecchi R (2016) ACKR2: an atypical chemokine receptor regulating lymphatic biology. Front Immunol 7, 691
  18. Freitas C, Desnoyer A, Meuris F, Bachelerie F, Balabanian K and Machelon V (2014) The relevance of the chemokine receptor ACKR3/CXCR7 on CXCL12-mediated effects in cancers with a focus on virus-related cancers. Cytokine Growth Factor Rev 25, 307-316 https://doi.org/10.1016/j.cytogfr.2014.04.006
  19. Novitzky-Basso I and Rot A (2012) Duffy antigen receptor for chemokines and its involvement in patterning and control of inflammatory chemokines. Front Immunol 3, 266
  20. Rot A (2005) Contribution of Duffy antigen to chemokine function. Cytokine Growth Factor Rev 16, 687-694 https://doi.org/10.1016/j.cytogfr.2005.05.011
  21. Peiper SC, Wang ZX, Neote K et al (1995) The Duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of Duffy negative individuals who lack the erythrocyte receptor. J Exp Med 181, 1311-1317 https://doi.org/10.1084/jem.181.4.1311
  22. Massara M, Bonavita O, Mantovani A, Locati M and Bonecchi R (2016) Atypical chemokine receptors in cancer: friends or foes? J Leukoc Biol 99, 927-933 https://doi.org/10.1189/jlb.3MR0915-431RR
  23. Jenkins BD, Martini RN and Hire R (2019) Atypical Chemokine receptor 1 (DARC/ACKR1) in breast tumors is associated with survival, circulating chemokines, tumor-infiltrating immune cells, and african ancestry. Cancer Epidemiol Biomarkers Prev 28, 690-700 https://doi.org/10.1158/1055-9965.EPI-18-0955
  24. Headland SE, Jones HR, D'Sa AS, Perretti M and Norling LV (2014) Cutting-edge analysis of extracellular micro-particles using ImageStream(X) imaging flow cytometry. Sci Rep 4, 5237
  25. Bandyopadhyay S, Zhan R, Chaudhuri A et al (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12, 933-938 https://doi.org/10.1038/nm1444
  26. Khanna P, Chung CY, Neves RI, Robertson GP and Dong C (2014) CD82/KAI expression prevents IL-8-mediated endothelial gap formation in late-stage melanomas. Oncogene 33, 2898-2908 https://doi.org/10.1038/onc.2013.249
  27. Hsu PD, Lander ES and Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262-1278 https://doi.org/10.1016/j.cell.2014.05.010
  28. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA and Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8, 2281-2308 https://doi.org/10.1038/nprot.2013.143
  29. Heckl D, Kowalczyk MS, Yudovich D et al (2014) Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat Biotechnol 32, 941-946 https://doi.org/10.1038/nbt.2951
  30. Ludin A, Itkin T, Gur-Cohen S et al (2012) Monocytes-macrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat Immunol 13, 1072-1082 https://doi.org/10.1038/ni.2408
  31. Upadhyay VA and Fathi AT (2018) Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions. Curr Opin Hematol 25, 67-74 https://doi.org/10.1097/MOH.0000000000000407
  32. Kantarjian H, Kadia T, DiNardo C et al (2021) Acute myeloid leukemia: current progress and future directions. Blood Cancer J 11, 41
  33. Jacobs AD and Gale RP (1987) Acute myelogenous leukemia following radiation therapy and chemotherapy for osteogenic sarcoma. Cancer Treat Rep 68, 909-911
  34. Vago L and Gojo I (2020) Immune escape and immunotherapy of acute myeloid leukemia. J Clin Invest 130, 1552-1564 https://doi.org/10.1172/JCI129204
  35. Chang YJ, Wang Y and Huang XJ (2014) Haploidentical stem cell transplantation for the treatment of leukemia: current status. Expert Rev Hematol 7, 635-647 https://doi.org/10.1586/17474086.2014.954543
  36. Barrett AJ and Battiwalla M (2010) Relapse after allogeneic stem cell transplantation. Expert Rev Hematol 3, 429-441 https://doi.org/10.1586/ehm.10.32
  37. Gribben JG, Zahrieh D, Stephans K et al (2005) Autologous and allogeneic stem cell transplantations for poorrisk chronic lymphocytic leukemia. Blood 106, 4389-4396 https://doi.org/10.1182/blood-2005-05-1778
  38. Niederwieser D, Baldomero H and Bazuaye N (2022) One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors. Haematologica 107, 1045-1053 https://doi.org/10.3324/haematol.2021.279189
  39. Sidney LE, Branch MJ, Dunphy SE, Dua HS and Hopkinson A (2014) Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells 32, 1380-1389 https://doi.org/10.1002/stem.1661
  40. Lee JY and Hong SH (2020) Hematopoietic stem cells and their roles in tissue regeneration. Int J Stem Cells 13, 1-12 https://doi.org/10.15283/ijsc19127
  41. Marcola M and Rodrigues CE (2015) Endothelial progenitor cells in tumor angiogenesis: another brick in the wall. Stem Cells Int 2015, 832649
  42. Elgarten CW and Aplenc R (2020) Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy. Curr Opin Pediatr 32, 57-66 https://doi.org/10.1097/MOP.0000000000000855
  43. Thol F and Ganser A (2020) Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol 21, 66
  44. Mayer IM, Hoelbl-Kovacic A, Sexl V and Doma E (2022) Isolation, maintenance and expansion of adult hematopoietic stem/progenitor cells and leukemic stem cells. Cancers (Basel) 14, 1723
  45. Tajer P, Cante-Barrett K, Naber BAE et al (2022) IL3 has a detrimental effect on hematopoietic stem cell self-renewal in transplantation settings. Int J Mol Sci 23, 12736