title: Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology, Nevada Cancer Institute, 1 Breakthrough Way, Las Vegas, NV 89135, USA. jyang@nvcancer.org
authors.forename: Jianchang
authors.initials: J
authors.lastname: Yang
authors.forename: Jerell R
authors.initials: JR
authors.lastname: Aguila
authors.forename: Zaida
authors.initials: Z
authors.lastname: Alipio
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Louis M
authors.initials: LM
authors.lastname: Fink
authors.forename: Yupo
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C509167:Sall4 protein, mouse; D014157:Transcription Factors