In vitro generation of HSC-like cells from murine ESCs/iPSCs by enforced expression of LIM-homeobox transcription factor Lhx2

Blood. 2011 Apr 7;117(14):3748-58. doi: 10.1182/blood-2010-07-298596. Epub 2011 Feb 22.

Abstract

Identification of genes involved in in vitro differentiation induction of embryonic stem cells (ESCs) into hematopoietic stem cells (HSCs) has been challenged during last decade. To date, a homeobox transcription factor Hoxb4 has been only demonstrated to possess such an effect in mice. Here, we show that HSC-like cells were efficiently induced from mouse ESCs by enforced expression of Lhx2, a LIM-homeobox transcription factor. Transduction of Lhx2 into ESC-derived mesodermal cells resulted in robust differentiation of c-Kit(+)/Sca-1(+)/Lineage(-) (KSL) cells in vitro. The KSL cell induction frequency was superior to the case of Hoxb4. Furthermore, transplantation of Lhx2-transduced hematopoietic cells into lethally irradiated mice resulted in multilineage repopulation of hematopoietic cells over 4 months. Transduction of Lhx2 into induced pluripotent stem cells (iPSCs) was also effective in generating KSL cells in vitro, as well as HSC-like activities in vivo. These results demonstrate that ectopic expression of Lhx2 confers an in vivo engrafting capacity to ESC/iPSC-derived hematopoietic cells and in vivo behavior of iPSC-derived hematopoietic cells is almost identical to that of ESC-derived cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • CHO Cells
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Embryo, Mammalian
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / physiology*
  • LIM-Homeodomain Proteins
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-kit / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Transfection

Substances

  • Antigens, Ly
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Lhx2 protein, mouse
  • Ly6a protein, mouse
  • Membrane Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-kit