Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4
Tóm tắt
Sall4 is a key factor for the maintenance of pluripotency and self-renewal of embryonic stem cells (ESCs). Our previous studies have shown that Sall4 is a robust stimulator for human hematopoietic stem and progenitor cell (HSC/HPC) expansion. The purpose of the current study is to further evaluate how Sall4 may affect HSC/HPC activities in a murine system. Lentiviral vectors expressing Sall4A or Sall4B isoform were used to transduce mouse bone marrow Lin-/Sca1+/c-Kit+ (LSK) cells and HSC/HPC self-renewal and differentiation were evaluated. Forced expression of Sall4 isoforms led to sustained ex vivo proliferation of LSK cells. In addition, Sall4 expanded HSC/HPCs exhibited increased in vivo repopulating abilities after bone marrow transplantation. These activities were associated with dramatic upregulation of multiple HSC/HPC regulatory genes including HoxB4, Notch1, Bmi1, Runx1, Meis1 and Nf-ya. Consistently, downregulation of endogenous Sall4 expression led to reduced LSK cell proliferation and accelerated cell differentiation. Moreover, in myeloid progenitor cells (32D), overexpression of Sall4 isoforms inhibited granulocytic differentiation and permitted expansion of undifferentiated cells with defined cytokines, consistent with the known functions of Sall4 in the ES cell system. Sall4 is a potent regulator for HSC/HPC self-renewal, likely by increasing self-renewal activity and inhibiting differentiation. Our work provides further support that Sall4 manipulation may be a new model for expanding clinically transplantable stem cells.
Tài liệu tham khảo
Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, Pear WS, Bernstein ID: Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000, 6: 1278-81. 10.1038/81390.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL: A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003, 423: 409-14. 10.1038/nature01593.
Antonchuk J, Sauvageau G, Humphries RK: HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell. 2002, 109: 39-45. 10.1016/S0092-8674(02)00697-9.
Kohlhase J, Schuh R, Dowe G, Kuhnlein RP, Jackle H, Schroeder B, Schulz-Schaeffer W, Kretzschmar HA, Kohler A, Muller U, Raab-Vetter M, Burkhardt E, Engel W, Stick R: Isolation, characterization, and organ-specific expression of two novel human zinc finger genes related to the Drosophila gene spalt. Genomics. 1996, 38: 291-8. 10.1006/geno.1996.0631.
Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC: Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002, 71: 1195-9. 10.1086/343821.
Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, Lou Y, Yang J, Ma Y, Chai L, Ng HH, Lufkin T, Robson P, Lim B: Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol. 2006, 8: 1114-23. 10.1038/ncb1481.
Yang J, Chai L, Fowles TC, Alipio Z, Xu D, Fink LM, Ward DC, Ma Y: Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proc Natl Acad Sci USA. 2008, 105: 19756-61. 10.1073/pnas.0809321105.
Wu Q, Chen X, Zhang J, Loh YH, Low TY, Zhang W, Sze SK, Lim B, Ng HH: Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem. 2006, 281: 24090-4. 10.1074/jbc.C600122200.
Lim CY, Tam WL, Zhang J, Ang HS, Jia H, Lipovich L, Ng HH, Wei CL, Sung WK, Robson P, Yang H, Lim B: Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell Stem Cell. 2008, 3: 543-54. 10.1016/j.stem.2008.08.004.
Elling U, Klasen C, Eisenberger T, Anlag K, Treier M: Murine inner cell mass-derived lineages depend on Sall4 function. Proc Natl Acad Sci USA. 2006, 103: 16319-24. 10.1073/pnas.0607884103.
Tsubooka N, Ichisaka T, Okita K, Takahashi K, Nakagawa M, Yamanaka S: Roles of Sall4 in the generation of pluripotent stem cells from blastocysts and fibroblasts. Genes Cells. 2009, 14: 683-94. 10.1111/j.1365-2443.2009.01301.x.
Wong CC, Gaspar-Maia A, Ramalho-Santos M, Reijo Pera RA: High-efficiency stem cell fusion-mediated assay reveals Sall4 as an enhancer of reprogramming. PLoS One. 2008, 3: e1955-10.1371/journal.pone.0001955.
Neff AW, King MW, Mescher AL: Dedifferentiation and the role of sall4 in reprogramming and patterning during amphibian limb regeneration. Dev Dyn. 2011, 240 (5): 979-89. 10.1002/dvdy.22554.
Rao S, Zhen S, Roumiantsev S, McDonald LT, Yuan GC, Orkin SH: Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Mol Cell Biol. 2010, 30: 5364-80. 10.1128/MCB.00419-10.
Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH: A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006, 444: 364-8. 10.1038/nature05284.
Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L: SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood. 2006, 108: 2726-35. 10.1182/blood-2006-02-001594.
Yang J, van Oosten AL, Theunissen TW, Guo G, Silva JC, Smith A: Stat3 activation is limiting for reprogramming to ground state pluripotency. Cell Stem Cell. 2010, 7: 319-28. 10.1016/j.stem.2010.06.022.
Oikawa T, Kamiya A, Kakinuma S, Zeniya M, Nishinakamura R, Tajiri H, Nakauchi H: Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells. Gastroenterology. 2009, 136: 1000-11. 10.1053/j.gastro.2008.11.018.
Aguila JR, Liao W, Yang J, Avila C, Hagag N, Senzel L, Ma Y: SALL4 is a robust stimulator for the expansion of hematopoietic stem cells. Blood. 2011, 118: 576-85. 10.1182/blood-2011-01-333641.
Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y: SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood. 2008, 112: 805-13. 10.1182/blood-2007-11-126326.
Xu D, Yoder M, Sutton J, Hromas R: Forced expression of Genesis, a winged helix transcriptional repressor isolated from embryonic stem cells, blocks granulocytic differentiation of 32D myeloid cells. Leukemia. 1998, 12: 207-12. 10.1038/sj.leu.2400948.
Milner LA, Bigas A, Kopan R, Brashem-Stein C, Bernstein ID, Martin DI: Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci USA. 1996, 93: 13014-9. 10.1073/pnas.93.23.13014.
Reya T: Regulation of hematopoietic stem cell self-renewal. Recent Prog Horm Res. 2003, 58: 283-95. 10.1210/rp.58.1.283.
Aglietta M, Bertolini F, Carlo-Stella C, De Vincentiis A, Lanata L, Lemoli RM, Olivieri A, Siena S, Zanon P, Tura S: Ex vivo expansion of hematopoietic cells and their clinical use. Haematologica. 1998, 83: 824-48.
Faubert A, Chagraoui J, Mayotte N, Frechette M, Iscove NN, Humphries RK, Sauvageau G: Complementary and independent function for Hoxb4 and Bmi1 in HSC activity. Cold Spring Harb Symp Quant Biol. 2008, 73: 555-64. 10.1101/sqb.2008.73.030.
Satoh Y, Matsumura I, Tanaka H, Ezoe S, Sugahara H, Mizuki M, Shibayama H, Ishiko E, Ishiko J, Nakajima K, Kanakura Y: Roles for c-Myc in self-renewal of hematopoietic stem cells. J Biol Chem. 2004, 279: 24986-93. 10.1074/jbc.M400407200.
Nakano T: Hematopoietic stem cells: generation and manipulation. Trends Immunol. 2003, 24: 589-94. 10.1016/j.it.2003.09.003.
Zhu J, Zhang Y, Joe GJ, Pompetti R, Emerson SG: NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci USA. 2005, 102: 11728-33. 10.1073/pnas.0503405102.
Zhu J, Giannola DM, Zhang Y, Rivera AJ, Emerson SG: NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4. Blood. 2003, 102: 2420-7. 10.1182/blood-2003-01-0251.
Pineault N, Helgason CD, Lawrence HJ, Humphries RK: Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002, 30: 49-57. 10.1016/S0301-472X(01)00757-3.
North TE, de Bruijn MF, Stacy T, Talebian L, Lind E, Robin C, Binder M, Dzierzak E, Speck NA: Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 2002, 16: 661-72. 10.1016/S1074-7613(02)00296-0.
Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H, van Lohuizen M, Nakauchi H: Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004, 21: 843-51. 10.1016/j.immuni.2004.11.004.
Neff AW, King MW, Mescher AL: Dedifferentiation and the role of sall4 in reprogramming and patterning during amphibian limb regeneration. Dev Dyn. 2011, 240: 979-89. 10.1002/dvdy.22554.
Takahashi K: Direct reprogramming 101. Dev Growth Differ. 2010, 52: 319-33. 10.1111/j.1440-169X.2010.01169.x.
VanBrocklin MW, Verhaegen M, Soengas MS, Holmen SL: Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res. 2009, 69: 1985-94. 10.1158/0008-5472.CAN-08-3934.
Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y: Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA. 2007, 104: 10494-9. 10.1073/pnas.0704001104.