Rentas S, Holzapfel N, Belew MS, Pratt G, Voisin V, Wilhelm BT, et al. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. Nature. 2016;532(7600):508–11.

Article  Google Scholar 

Hope KJ, Cellot S, Ting SB, MacRae T, Mayotte N, Iscove NN, et al. An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity. Cell Stem Cell. 2010;7(1):101–13.

CAS  Article  Google Scholar 

de Andres-Aguayo L, Varas F, Kallin EM, Infante JF, Wurst W, Floss T, et al. Musashi 2 is a regulator of the HSC compartment identified by a retroviral insertion screen and knockout mice. Blood. 2011;118(3):554–64.

Article  Google Scholar 

Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010;16(8):903–8.

CAS  Article  Google Scholar 

Belew MS, Bhatia S, Keyvani Chahi A, Rentas S, Draper JS, Hope KJ. PLAG1 and USF2 co-regulate expression of Musashi-2 in human hematopoietic stem and progenitor cells. Stem Cell Reports. 2018;10(4):1384–97.

CAS  Article  Google Scholar 

Angelos MG, Kaufman DS. Advances in the role of the aryl hydrocarbon receptor to regulate early hematopoietic development. Curr Opin Hematol. 2018;25(4):273–8.

CAS  Article  Google Scholar 

Angelos MG, Ruh PN, Webber BR, Blum RH, Ryan CD, Bendzick L, et al. Aryl hydrocarbon receptor inhibition promotes hematolymphoid development from human pluripotent stem cells. Blood. 2017;129(26):3428–39.

CAS  Article  Google Scholar 

Wagner JE Jr, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, et al. Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell. 2016;18(1):144–55.

CAS  Article  Google Scholar 

Cohen S, Roy J, Lachance S, Delisle JS, Marinier A, Busque L, et al. Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1–2 safety and feasibility study. Lancet Haematol. 2020;7(2):e134–45.

Article  Google Scholar 

Mesquitta WT, Wandsnider M, Kang H, Thomson J, Moskvin O, Suknuntha K, et al. UM171 expands distinct types of myeloid and NK progenitors from human pluripotent stem cells. Sci Rep. 2019;9(1):6622.

Article  Google Scholar 

Li X, Xia C, Wang T, Liu L, Zhao Q, Yang D, et al. Pyrimidoindole derivative UM171 enhances derivation of hematopoietic progenitor cells from human pluripotent stem cells. Stem Cell Res. 2017;21:32–9.

CAS  Article  Google Scholar 

Ngom M, Imren S, Maetzig T, Adair JE, Knapp D, Chagraoui J, et al. UM171 enhances lentiviral gene transfer and recovery of primitive human hematopoietic cells. Mol Ther Methods Clin Dev. 2018;10:156–64.

CAS  Article  Google Scholar 

Chagraoui J, Lehnertz B, Girard S, Spinella JF, Fares I, Tomellini E, et al. UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal. PLoS One. 2019;14(11):e0224900.

•• Subramaniam A, Zemaitis K, Talkhoncheh MS, Yudovich D, Backstrom A, Debnath S, et al. Lysine-specific demethylase 1A restricts ex vivo propagation of human HSCs and is a target of UM171. Blood. 2020;136(19):2151–61. This study demonstrates that inhibition of LSD1 promotes the expansion of human HSC by blocking differentiation. They find that LSD1 and other members of CoREST are polyubiquitinated and degraded upon UM171 treatment, which provide a mechanism of action for UM171 in stimulating HSC expansion.

•• Chagraoui J, Girard S, Spinella JF, Simon L, Bonneil E, Mayotte N, et al. UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex. Cell Stem Cell. 2021;28(1):48–62 e6. This study shows that UM171 induces human HSPC expansion by targeting RCOR1 and LSD1 protein degradation through CULLIN3KBTBD4 ubiquitin ligase.

Sprussel A, Schulte JH, Weber S, Necke M, Handschke K, Thor T, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039–51.

CAS  Article  Google Scholar 

Kerenyi MA, Shao Z, Hsu YJ, Guo G, Luc S, O'Brien K, et al. Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife. 2013;2:e00633.

Yu L, Myers G, Ku C-J, Schneider E, Wang Y, Singh SA, et al. The epigenetic eraser LSD1 lies at the apex of a reversible erythroid to myeloid cell fate decision. bioRxiv. 2021:2021.01.13.426552.

Papa L, Zimran E, Djedaini M, Ge Y, Ozbek U, Sebra R, et al. Ex vivo human HSC expansion requires coordination of cellular reprogramming with mitochondrial remodeling and p53 activation. Blood Adv. 2018;2(20):2766-79. 

•• Zimran E, Papa L, Djedaini M, Patel A, Iancu-Rubin C, Hoffman R. Expansion and preservation of the functional activity of adult hematopoietic stem cells cultured ex vivo with a histone deacetylase inhibitor. Stem Cells Transl Med. 2020;9(4):531-42. This study shows that human HSPCs expanded with HDAC inhibitor retain the primitive HSC phenotype and maintain a transcriptomic and mitochondrial profile similar to uncultured HSCs.

Liang R, Arif T, Kalmykova S, Kasianov A, Lin M, Menon V, et al. Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency. Cell Stem Cell. 2020;26(3):359–76 e7.

Vannini N, Girotra M, Naveiras O, Nikitin G, Campos V, Giger S, et al. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat Commun. 2016;7:13125.

CAS  Article  Google Scholar 

Wroblewski M, Scheller-Wendorff M, Udonta F, Bauer R, Schlichting J, Zhao L, et al. BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells. Haematologica. 2018;103(6):939–48.

CAS  Article  Google Scholar 

Dey A, Yang W, Gegonne A, Nishiyama A, Pan R, Yagi R, et al. BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses. EMBO J. 2019;38(7).

•• Hua P, Hester J, Adigbli G, Li R, Psaila B, Roy A, et al. The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes. Blood. 2020;136(21):2410–5. This study shows that BET inhibition is a promising epigenetic modification that induces HSC expansion and megakaryocytic maturation.

Fong CY, Gilan O, Lam EY, Rubin AF, Ftouni S, Tyler D, et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature. 2015;525(7570):538–42.

CAS  Article  Google Scholar 

Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525(7570):543–7.

CAS  Article  Google Scholar 

Engelke CG, Chinnaiyan AM. aBETting therapeutic resistance by Wnt signaling. Cell Res. 2015;25(11):1187–8.

Article  Google Scholar 

Auletta JJ, Lazarus HM. Immune restoration following hematopoietic stem cell transplantation: an evolving target. Bone Marrow Transplant. 2005;35(9):835–57.

CAS  Article  Google Scholar 

Glimm H, Oh IH, Eaves CJ. Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G(2)/M transit and do not reenter G(0). Blood. 2000;96(13):4185–93.

CAS  Article  Google Scholar 

Giralt S, Bishop MR. Principles and overview of allogeneic hematopoietic stem cell transplantation. Cancer Treat Res. 2009;144:1–21.

CAS  Article  Google Scholar 

Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577):1947–54.

Article  Google Scholar 

Balassa K, Danby R, Rocha V. Haematopoietic stem cell transplants: principles and indications. Br J Hosp Med (Lond). 2019;80(1):33–9.

Article  Google Scholar 

Fuchs EJ, O’Donnell PV, Eapen M, Logan B, Antin JH, Dawson P, et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood. 2021;137(3):420–8.

CAS  Article  Google Scholar 

Garcia JG, Grillo S, Cao Q, Brunstein CG, Arora M, MacMillan ML, et al. Low 5-year health care burden after umbilical cord blood transplantation. Blood Adv. 2021;5(3):853–60.

Article  Google Scholar 

Pineault N, Abu-Khader A. Advances in umbilical cord blood stem cell expansion and clinical translation. Exp Hematol. 2015;43(7):498–513.

Article  Google Scholar 

Liu H, Rich ES, Godley L, Odenike O, Joseph L, Marino S, et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood. 2011;118(24):6438–45.

CAS  Article  Google Scholar 

Kwon M, Bautista G, Balsalobre P, Sanchez-Ortega I, Serrano D, Anguita J, et al. Haplo-cord transplantation using CD34+ cells from a third-party donor to speed engraftment in high-risk patients with hematologic disorders. Biol Blood Marrow Transplant. 2014;20(12):2015–22.

CAS  Article  Google Scholar 

Politikos I, Devlin SM, Arcila ME, Barone JC, Maloy MA, Naputo KA, et al. Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin. Leukemia. 2021;35(3):850–62.

CAS  Article  Google Scholar 

Sica RA, Terzioglu MK, Mahmud D, Mahmud N. Mechanistic Basis of ex Vivo Umbilical Cord Blood Stem Progenitor Cell Expansion. Stem Cell Rev Rep. 2020;16(4):628–38.

Article  Google Scholar 

Wilkinson AC, Igarashi KJ, Nakauchi H. Haematopoietic stem cell self-renewal in vivo and ex vivo. Nat Rev Genet. 2020;21(9):541–54.

CAS  Article  Google Scholar 

Demirci S, Leonard A, Tisdale JF. Hematopoietic stem cells from pluripotent stem cells: Clinical potential, challenges, and future perspectives. Stem Cells Transl Med. 2020;9(12):1549–57.

Article  Google Scholar 

Gao X, Xu C, Asada N, Frenette PS. The hematopoietic stem cell niche: from embryo to adult. Development. 2018;145(2).

Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333(6039):218–21.

CAS  Article  Google Scholar 

Prashad SL, Calvanese V, Yao CY, Kaiser J, Wang Y, Sasidharan R, et al. GPI-80 defines self-renewal ability in hematopoietic stem cells during human development. Cell Stem Cell. 2015;16(1):80–7.

CAS  Article  Google Scholar 

Vanuytsel K, Villacorta-Martin C, Lindstrom-Vautrin J, Wang Z, Garcia-Beltran WF, Vrbanac V, et al. Multi-modal profiling of human fetal liver-derived hematopoietic stem cells reveals the molecular signature of engraftment potential. bioRxiv. 2020:11.378620.

Fares I, Chagraoui J, Lehnertz B, MacRae T, Mayotte N, Tomellini E, et al. EPCR expression marks UM171-expanded CD34(+) cord blood stem cells. Blood. 2017;129(25):3344–51.

CAS  Article  Google Scholar 

Psatha N, Georgolopoulos G, Phelps S, Papayannopoulou T. Brief Report: A differential transcriptomic profile of ex vivo expanded adult human hematopoietic stem cells empowers them for engraftment better than their surface phenotype. Stem Cells Transl Med. 2017;6(10):1852–8.

CAS  Article  Google Scholar 

Chen Y, Yao C, Teng Y, Jiang R, Huang X, Liu S, et al. Phorbol ester induced ex vivo expansion of rigorously-defined phenotypic but not functional human cord blood hematopoietic stem cells: a cautionary tale demonstrating that phenotype does not always recapitulate stem cell function. Leukemia. 2019;33(12):2962–6.

Article  Google Scholar 

Magnusson M, Sierra MI, Sasidharan R, Prashad SL, Romero M, Saarikoski P, et al. Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability. PLoS One. 2013;8(1):e53912.

Balazs AB, Fabian AJ, Esmon CT, Mulligan RC. Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood. 2006;107(6):2317–21.

CAS  Article  Google Scholar 

Gur-Cohen S, Itkin T, Chakrabarty S, Graf C, Kollet O, Ludin A, et al. Corrigendum: PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med. 2016;22(4):446.

CAS  Article  Google Scholar 

Subramaniam A, Talkhoncheh MS, Magnusson M, Larsson J. Endothelial protein C receptor (EPCR) expression marks human fetal liver hematopoietic stem cells. Haematologica. 2019;104(2):e47-e50. 

• Tomellini E, Fares I, Lehnertz B, Chagraoui J, Mayotte N, MacRae T, et al. Integrin-alpha3 is a functional marker of ex vivo expanded human long-term hematopoietic stem cells. Cell Rep. 2019;28(4):1063-73 e5. This study shows that EPCR+ HSPCs are a heterogenous population and can be further separated into long- and short-term repopulating cells based on ITGA3 expression.

Upadhaya S, Reizis B, Sawai CM. New genetic tools for the in vivo study of hematopoietic stem cell function. Exp Hematol. 2018;61:26–35.

CAS  Article  Google Scholar 

Lehnertz B, Chagraoui J, MacRae T, Tomellini E, Corneau S, Mayotte N, et al. HLF expression defines the human hematopoietic stem cell state. Blood. 2021.

• Papa L, Djedaini M, Martin TC, Zangui M, Beaumont KG, Sebra R, et al. Limited mitochondrial activity coupled with strong expression of CD34, CD90 and EPCR determines the functional fitness of ex vivo expanded human hematopoietic stem cells. Front Cell Dev Biol. 2020;8:592348. This study demonstrates that human long-term HSC can be distinguished from other cell types in expansion cultures by having low mitochondrial activity and high expression of CD34, CD90 and EPCR surface phenotype.

Ghaffari S. Lysosomal regulation of metabolism in quiescent hematopoietic stem cells: more than just autophagy. Cell Stem Cell. 2021;28(3):374–7.

CAS  Article  Google Scholar 

Garcia-Prat L, Kaufmann KB, Schneiter F, Voisin V, Murison A, Chen J, et al. TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate. Cell Stem Cell. 2021;28(10):1838–50 e10.

van Galen P, Mbong N, Kreso A, Schoof EM, Wagenblast E, Ng SWK, et al. Integrated stress response activity marks stem cells in normal hematopoiesis and leukemia. Cell Rep. 2018;25(5):1109–17 e5.

Liu L, Zhao M, Jin X, Ney G, Yang KB, Peng F, et al. Adaptive endoplasmic reticulum stress signalling via IRE1alpha-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells. Nat Cell Biol. 2019;21(3):328–37.

CAS  Article