Stem cell biology

Hematopoietic stem and progenitor cell signaling in the niche


Hematopoietic stem and progenitor cells (HSPCs) are responsible for lifelong maintenance of hematopoiesis through self-renewal and differentiation into mature blood cell lineages. Traditional models hold that HSPCs guard homeostatic function and adapt to regenerative demand by integrating cell-autonomous, intrinsic programs with extrinsic cues from the niche. Despite the biologic significance, little is known about the active roles HSPCs partake in reciprocally shaping the function of their microenvironment. Here, we review evidence of signals emerging from HSPCs through secreted autocrine or paracrine factors, including extracellular vesicles, and via direct contact within the niche. We also discuss the functional impact of direct cellular interactions between hematopoietic elements on niche occupancy in the context of leukemic infiltration. The aggregate data support a model whereby HSPCs are active participants in the dynamic adaptation of the stem cell niche unit during development and homeostasis, and under inflammatory stress, malignancy, or transplantation.

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Fig. 1: Autocrine signals provide multiple mechanisms of governing hematopoietic stem and progenitor cell function.
Fig. 2: Hematopoietic stem and progenitor cells actively modulate cells in their bone marrow niche.
Fig. 3: Cell-cell competition drives predominance of the “fittest” hematopoietic cells.
Fig. 4: Extracellular vesicles mediate crosstalk in the bone marrow microenvironment.


  1. 1.

    Laurenti E, Göttgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018;553:418–26.

  2. 2.

    Cheshier SH, Morrison SJ, Liao X, Weissman IL. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA. 1999;96:3120–5.

    CAS  PubMed  Google Scholar 

  3. 3.

    Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014;15:37–50. 2014/05/08 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Frisch BJ. The hematopoietic stem cell niche: what’s so special about bone? Bone. 2018/05/17 ed. 2019;119:8–12.

  5. 5.

    Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010;6:251–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Yu VW, Scadden DT. Hematopoietic Stem Cell and Its Bone Marrow Niche. Curr Top Dev Biol. 2016;118:21–44. 2016/03/21 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–61.

    CAS  PubMed  Google Scholar 

  8. 8.

    Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–97. 2007/11/20 ed.

    CAS  PubMed  Google Scholar 

  9. 9.

    Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977–88.

    CAS  PubMed  Google Scholar 

  10. 10.

    Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014;20:1315–20. 2014/10/19 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116:4815–28.

    CAS  PubMed  Google Scholar 

  12. 12.

    Parekh C, Crooks GM. Critical differences in hematopoiesis and lymphoid development between humans and mice. J Clin Immunol. 2013;33:711–5. 2012/12/30 ed.

    CAS  PubMed  Google Scholar 

  13. 13.

    Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA, et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood. 2001;97:3075–85.

    CAS  PubMed  Google Scholar 

  14. 14.

    Janowska-Wieczorek A, Majka M, Ratajczak J, Ratajczak MZ. Autocrine/paracrine mechanisms in human hematopoiesis. Stem Cells. 2001;19:99–107.

    CAS  PubMed  Google Scholar 

  15. 15.

    Ratajczak MZ, Kuczynski WI, Sokol DL, Moore JS, Pletcher CH, Gewirtz AM. Expression and physiologic significance of Kit ligand and stem cell tyrosine kinase-1 receptor ligand in normal human CD34+, c-Kit+ marrow cells. Blood. 1995;86:2161–7.

    CAS  PubMed  Google Scholar 

  16. 16.

    Behringer D, Kresin V, Henschler R, Mertelsmann R, Lindemann A. Cytokine and chemokine production by CD34+ haemopoietic progenitor cells: detection in single cells. Br J Haematol. 1997;97:9–14.

    CAS  PubMed  Google Scholar 

  17. 17.

    Kim H, Whartenby KA, Georgantas RW, Wingard J, Civin CI. Human CD34+ hematopoietic stem/progenitor cells express high levels of FLIP and are resistant to Fas-mediated apoptosis. Stem Cells. 2002;20:174–82.

    CAS  PubMed  Google Scholar 

  18. 18.

    Ratajczak MZ, Bujko K, Cymer M, Thapa A, Adamiak M, Ratajczak J, et al. The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis. Leukemia. 2020;34:1512–23.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Gerber H-P, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.

    CAS  PubMed  Google Scholar 

  20. 20.

    Kirito K, Fox N, Komatsu N, Kaushansky K. Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1alpha. Blood. 2005;105:4258–63. 2005/02/10 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Browder TM, Abrams JS, Wong PM, Nienhuis AW. Mechanism of autocrine stimulation in hematopoietic cells producing interleukin-3 after retrovirus-mediated gene transfer. Mol Cell Biol. 1989;9:204–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Müller E, Wang W, Qiao W, Bornhäuser M, Zandstra PW, Werner C, et al. Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform. Sci Rep. 2016/08/18 ed. 2016;6:31951.

  23. 23.

    Qiao W, Wang W, Laurenti E, Turinsky AL, Wodak SJ, Bader GD, et al. Intercellular network structure and regulatory motifs in the human hematopoietic system. Mol Syst Biol. 2014;10:741. 2014/07/15 ed.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Han W, Yu Y, Liu XY. Local signals in stem cell-based bone marrow regeneration. Cell Res. 2006;16:189–95.

    PubMed  Google Scholar 

  25. 25.

    Sitnicka E, Ruscetti FW, Priestley GV, Wolf NS, Bartelmez SH. Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells. Blood. 1996;88:82–8.

    CAS  PubMed  Google Scholar 

  26. 26.

    Langer JC, Henckaerts E, Orenstein J, Snoeck HW. Quantitative trait analysis reveals transforming growth factor-beta2 as a positive regulator of early hematopoietic progenitor and stem cell function. J Exp Med. 2004;199:5–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ruscetti FW, Akel S, Bartelmez SH. Autocrine transforming growth factor- β regulation of hematopoiesis: many outcomes that depend on the context. Oncogene. 2005;24:5751–63.

    CAS  PubMed  Google Scholar 

  28. 28.

    Larsson J, Blank U, Helgadottir H, Björnsson JM, Ehinger M, Goumans MJ, et al. TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood. 2003;102:3129–35. 2003/07/03 ed.

    CAS  PubMed  Google Scholar 

  29. 29.

    Challen GA, Boles NC, Chambers SM, Goodell MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010;6:265–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Konrad L, Scheiber JA, Völck-Badouin E, Keilani MM, Laible L, Brandt H, et al. Alternative splicing of TGF-betas and their high-affinity receptors T beta RI, T beta RII and T beta RIII (betaglycan) reveal new variants in human prostatic cells. BMC Genom. 2007;8:318. 2007/09/11 ed.

    Google Scholar 

  31. 31.

    Lemischka IR, Pritsker M. Alternative splicing increases complexity of stem cell transcriptome. Cell Cycle. 2006;5:347–51. 2006/02/15 ed.

    CAS  PubMed  Google Scholar 

  32. 32.

    Ficara F, Murphy MJ, Lin M, Cleary ML. Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell. 2008;2:484–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Tipping AJ, Pina C, Castor A, Hong D, Rodrigues NP, Lazzari L, et al. High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. Blood. 2009;113:2661–72. 2009/01/23 ed.

    CAS  PubMed  Google Scholar 

  34. 34.

    Li J. Quiescence regulators for hematopoietic stem cell. Exp Hematol. 2011;39:511–20. 2011/02/01 ed.

    PubMed  Google Scholar 

  35. 35.

    Lacombe J, Krosl G, Tremblay M, Gerby B, Martin R, Aplan PD, et al. Genetic interaction between Kit and Scl. Blood. 2013;122:1150–61. 2013/07/08 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Benyoucef A, Calvo J, Renou L, Arcangeli ML, van den Heuvel A, Amsellem S, et al. The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells. Stem Cells. 2015;33:2268–79. 2015/05/25 ed.

    CAS  PubMed  Google Scholar 

  37. 37.

    Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18:2747–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Doğaner BA, Yan LKQ, Youk H. Autocrine signaling and quorum sensing: extreme ends of a common spectrum. Trends Cell Biol. 2016;26:262–71. 2015/12/05 ed.

    PubMed  Google Scholar 

  39. 39.

    Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell. 2014;15:507–22. 2014/08/21 ed.

    CAS  PubMed  Google Scholar 

  40. 40.

    Yu VWC, Yusuf RZ, Oki T, Wu J, Saez B, Wang X, et al. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell. 2016;167:1310–.e17.

    CAS  PubMed  Google Scholar 

  41. 41.

    Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.

    CAS  PubMed  Google Scholar 

  42. 42.

    Taichman RS, Reilly MJ, Verma RS, Emerson SG. Augmented production of interleukin-6 by normal human osteoblasts in response to CD34+ hematopoietic bone marrow cells in vitro. Blood. 1997;89:1165–72.

    CAS  PubMed  Google Scholar 

  43. 43.

    Gillette JM, Larochelle A, Dunbar CE, Lippincott-Schwartz J. Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche. Nat Cell Biol. 2009;11:303–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Jung Y, Song J, Shiozawa Y, Wang J, Wang Z, Williams B, et al. Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells. 2008;26:2042–51.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Lymperi S, Ersek A, Ferraro F, Dazzi F, Horwood NJ. Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood. 2011;117:1540–9.

    CAS  PubMed  Google Scholar 

  46. 46.

    Miyamoto K, Yoshida S, Kawasumi M, Hashimoto K, Kimura T, Sato Y, et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J Exp Med. 2011;208:2175–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Dürig J, Rosenthal C, Halfmeyer K, Wiemann M, Novotny J, Bingmann D, et al. Intercellular communication between bone marrow stromal cells and CD34+ haematopoietic progenitor cells is mediated by connexin 43-type gap junctions. Br J Haematol. 2000;111:416–25.

    PubMed  Google Scholar 

  48. 48.

    Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, et al. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci USA. 2012;109:9071–6. 2012/05/18 ed.

    PubMed  Google Scholar 

  49. 49.

    Zhou BO, Ding L, Morrison SJ. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. Elife. 2015;4:e05521. 2015/03/30 ed.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Prendergast ÁM, Kuck A, van Essen M, Haas S, Blaszkiewicz S, Essers MAG. IFNα-mediated remodeling of endothelial cells in the bone marrow niche. Haematologica. 2017;102:445–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Tamplin OJ, Durand EM, Carr LA, Childs SJ, Hagedorn EJ, Li P, et al. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell. 2015;160:241–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Amoyel M, Bach EA. Cell competition: how to eliminate your neighbours. Development. 2014;141:988–1000.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Ellis SJ, Gomez NC, Levorse J, Mertz AF, Ge Y, Fuchs E. Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature. 2019;569:497–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Morata G, Ripoll P. Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol. 1975;42:211–21.

    CAS  PubMed  Google Scholar 

  55. 55.

    Bondar T, Medzhitov R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell. 2010;6:309–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Zhang G, Xie Y, Zhou Y, Xiang C, Chen L, Zhang C, et al. p53 pathway is involved in cell competition during mouse embryogenesis. Proc Natl Acad Sci USA. 2017;114:498–503. 2017/01/03 ed.

  57. 57.

    Marusyk A, Porter CC, Zaberezhnyy V, DeGregori J. Irradiation selects for p53-deficient hematopoietic progenitors. PLoS Biol. 2010;8:e1000324.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Baker NE, Kiparaki M, Khan C. A potential link between p53, cell competition and ribosomopathy in mammals and in Drosophila. Dev Biol. 2019;446:17–9. 2018/12/02 ed.

  59. 59.

    Neves J, Demaria M, Campisi J, Jasper H. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging. Dev Cell. 2015;32:9–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Ito T, Igaki T. Dissecting cellular senescence and SASP in Drosophila. Inflamm Regen. 2016;36:25.

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, et al. Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner. Dev Cell. 2015;34:297–309. 2015/07/23 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15:978–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Murakami JL, Xu B, Franco CB, Hu X, Galli SJ, Weissman IL, et al. Evidence that β7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1. Stem Cells Dev. 2016;25:18–26. 2015/11/05 ed.

    CAS  PubMed  Google Scholar 

  64. 64.

    Smith-Berdan S, Nguyen A, Hassanein D, Zimmer M, Ugarte F, Ciriza J, et al. Robo4 Cooperates with Cxcr4 to Specify Hematopoietic Stem Cell Localization to Bone Marrow Niches. Cell Stem Cell. 2011;8:72–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Boyd AL, Campbell CJV, Hopkins CI, Fiebig-Comyn A, Russell J, Ulemek J, et al. Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs. J Exp Med. 2014;211:1925–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Boyd AL, Reid JC, Salci KR, Aslostovar L, Benoit YD, Shapovalova Z, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19:1336–47. 2017/10/16 ed.

    CAS  PubMed  Google Scholar 

  67. 67.

    Wagstaff L, Kolahgar G, Piddini E. Competitive cell interactions in cancer: a cellular tug of war. Trends Cell Biol. 2013;23:160–7. 2012/12/04 ed.

    CAS  PubMed  Google Scholar 

  68. 68.

    Glait-Santar C, Desmond R, Feng X, Bat T, Chen J, Heuston E, et al. Functional Niche Competition Between Normal Hematopoietic Stem and Progenitor Cells and Myeloid Leukemia Cells. Stem Cells. 2015;33:3635–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Tabe Y, Konopleva M. Leukemia Stem Cells Microenvironment. Adv Exp Med Biol. 2017;1041:19–32.

    CAS  PubMed  Google Scholar 

  70. 70.

    Moreno E, Basler K. dMyc transforms cells into super-competitors. Cell. 2004;117:117–29.

    CAS  PubMed  Google Scholar 

  71. 71.

    Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, et al. Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood. 2019;133:446–56. 2018/11/06 ed.

  72. 72.

    Abdelhamed S, Butler JT, Doron B, Halse A, Nemecek E, Wilmarth PA, et al. Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche. EMBO Rep [Internet]. 2019;20.

  73. 73.

    Caivano A, La Rocca F, Simeon V, Girasole M, Dinarelli S, Laurenzana I, et al. MicroRNA-155 in serum-derived extracellular vesicles as a potential biomarker for hematologic malignancies - a short report. Cell Oncol (Dordr). 2017;40:97–103. 2016/10/19 ed.

    CAS  Google Scholar 

  74. 74.

    Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA, Shen R, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016/09/06 ed. 2016;9:ra88.

  75. 75.

    Waclawiczek A, Hamilton A, Rouault-Pierre K, Abarrategi A, Albornoz MG, Miraki-Moud F, et al. Mesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia. J Clin Investig. [Internet]. 2020/05/04 ed. 2020.

  76. 76.

    Akinduro O, Weber TS, Ang H, Haltalli MLR, Ruivo N, Duarte D, et al. Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space. Nat Commun. 2;9:519. 2018/02/06 ed.

  77. 77.

    Pando A, Reagan JL, Quesenberry P. Fast LD Extracellular vesicles in leukemia. Leuk Res. 2018;64:52–60. 2017/11/22 ed.

  78. 78.

    Gu H, Chen C, Hao X, Wang C, Zhang X, Li Z, et al. Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. J Clin Investig. 2016;126:4537–53.

  79. 79.

    Lechman ER, Gentner B, Ng SWK, Schoof EM, van Galen P, Kennedy JA, et al. miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells. Cancer Cell. 2016;29:602–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, et al. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res. 2011;109:724–8. 2011/08/11 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Mathiyalagan P, Liang Y, Kim D, Misener S, Thorne T, Kamide CE, et al. Angiogenic Mechanisms of Human CD34. Circ Res. 2017;120:1466–76. 2017/03/15 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Butler JT, Abdelhamed S, Kurre P. Extracellular vesicles in the hematopoietic microenvironment. Haematologica. 2018;103:382–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Stik G, Crequit S, Petit L, Durant J, Charbord P, Jaffredo T, et al. Extracellular vesicles of stromal origin target and support hematopoietic stem and progenitor cells. J Cell Biol. 2017/06/19 ed. 2017;216:2217–30.

  84. 84.

    De Luca L, Trino S, Laurenzana I, Simeon V, Calice G, Raimondo S, et al. MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: a new insight in transplantation. Oncotarget. 2016;7:6676–92.

    PubMed  Google Scholar 

  85. 85.

    Janowska-Wieczorek A, Majka M, Kijowski J, Baj-Krzyworzeka M, Reca R, Turner AR, et al. Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment. Blood. 2001;98:3143–9.

    CAS  PubMed  Google Scholar 

  86. 86.

    Lyman SD, James L, Escobar S, Downey H, de Vries P, Brasel K, et al. Identification of soluble and membrane-bound isoforms of the murine flt3 ligand generated by alternative splicing of mRNAs. Oncogene. 1995;10:149–57.

    CAS  PubMed  Google Scholar 

  87. 87.

    Hurwitz SN, Rider MA, Bundy JL, Liu X, Singh RK, Meckes DG. Proteomic profiling of NCI-60 extracellular vesicles uncovers common protein cargo and cancer type-specific biomarkers. Oncotarget. 2016;7:86999–7015.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Bauer N, Wilsch-Bräuninger M, Karbanová J, Fonseca AV, Strauss D, Freund D, et al. Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133-containing membrane vesicles-a role of the endocytic-exocytic pathway. EMBO Mol Med. 2011;3:398–409. 2011/05/18 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Holmfeldt P, Ganuza M, Marathe H, He B, Hall T, Kang G, et al. Functional screen identifies regulators of murine hematopoietic stem cell repopulation. J Exp Med. 2016;213:433–49.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Liao F, Tan L, Liu H, Wang J, Ma X, Zhao B, et al. Hematopoietic stem cell-derived exosomes promote hematopoietic differentiation of mouse embryonic stem cells in vitro via inhibiting the miR126/Notch1 pathway. Acta Pharm Sin. 2018;39:552–60.

    CAS  Google Scholar 

  91. 91.

    Lechman ER, Gentner B, van Galen P, Giustacchini A, Saini M, Boccalatte FE, et al. Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell. 2012;11:799–811. 2012/11/08 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Salvucci O, Jiang K, Gasperini P, Maric D, Zhu J, Sakakibara S, et al. MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1. Haematologica. 2012;97:818–26. 2012/01/22 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Ratajczak J, Kucia M, Mierzejewska K, Marlicz W, Pietrzkowski Z, Wojakowski W, et al. Paracrine proangiopoietic effects of human umbilical cord blood-derived purified CD133+ cells-implications for stem cell therapies in regenerative medicine. Stem Cells Dev. 2013;22:422–30. 2012/11/05 ed.

    CAS  PubMed  Google Scholar 

  94. 94.

    Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S, et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun. 2017/05/16 ed. 2017;8:15287.

  95. 95.

    Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010;7:174–85. 2010/07/08 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Koschade SE, Brandts CH. Selective Autophagy in Normal and Malignant Hematopoiesis. J Mol Biol. 2020;432:261–82. 2019/06/28 ed.

    CAS  PubMed  Google Scholar 

  97. 97.

    Xu J, Camfield R, Gorski SM. The interplay between exosomes and autophagy - partners in crime. J Cell Sci. [Internet]. 2018;131. 2018/08/03 ed.

  98. 98.

    Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. 2015/10/07 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Borghesan M, Fafián-Labora J, Eleftheriadou O, Carpintero-Fernández P, Paez-Ribes M, Vizcay-Barrena G, et al. Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3. Cell Rep. 2019;27:3956–71.e6.

  100. 100.

    Zhao JL, Ma C, O’Connell RM, Mehta A, DiLoreto R, Heath JR, et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell. 2014;14:445–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Denkinger MD, Leins H, Schirmbeck R, Florian MC, Geiger H. HSC Aging and Senescent Immune Remodeling. Trends Immunol. 2015;36:815–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011;208:2691–703. 2011/11/21 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Kim MJ, Kim MH, Kim SA, Chang JS. Age-related Deterioration of Hematopoietic Stem Cells. Int J Stem Cells. 2008;1:55–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16. 2015/04/30 ed.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Sieburg HB, Rezner BD, Muller-Sieburg CE. Predicting clonal self-renewal and extinction of hematopoietic stem cells. Proc Natl Acad Sci USA. 2011;108:4370–5. 2011/02/28 ed.

    CAS  PubMed  Google Scholar 

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We thank Dr. Peter S. Klein for careful review of the paper and editorial contributions. We also acknowledge many colleagues whose relevant research in the field we were not able to cite due to space limitations.

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Correspondence to Peter Kurre.

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Hurwitz, S.N., Jung, S.K. & Kurre, P. Hematopoietic stem and progenitor cell signaling in the niche. Leukemia 34, 3136–3148 (2020).

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