Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration

Blood. 2012 Jun 7;119(23):5429-37. doi: 10.1182/blood-2011-11-393645. Epub 2012 May 2.

Abstract

The BM microenvironment is required for the maintenance, proliferation, and mobilization of hematopoietic stem and progenitor cells (HSPCs), both during steady-state conditions and hematopoietic recovery after myeloablation. The ECM meshwork has long been recognized as a major anatomical component of the BM microenvironment; however, the molecular signatures and functions of the ECM to support HSPCs are poorly understood. Of the many ECM proteins, the expression of tenascin-C (TN-C) was found to be dramatically up-regulated during hematopoietic recovery after myeloablation. The TN-C gene was predominantly expressed in stromal cells and endothelial cells, known as BM niche cells, supporting the function of HSPCs. Mice lacking TN-C (TN-C(-/-)) mice showed normal steady-state hematopoiesis; however, they failed to reconstitute hematopoiesis after BM ablation and showed high lethality. The capacity to support transplanted wild-type hematopoietic cells to regenerate hematopoiesis was reduced in TN-C(-/-) recipient mice. In vitro culture on a TN-C substratum promoted the proliferation of HSPCs in an integrin α9-dependent manner and up-regulated the expression of the cyclins (cyclinD1 and cyclinE1) and down-regulated the expression of the cyclin-dependent kinase inhibitors (p57(Kip2), p21(Cip1), p16(Ink4a)). These results identify TN-C as a critical component of the BM microenvironment that is required for hematopoietic regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism*
  • Bone Marrow / radiation effects
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Gene Deletion
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Integrin alpha Chains / genetics
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Tenascin / analysis
  • Tenascin / genetics
  • Tenascin / metabolism*
  • Up-Regulation
  • Whole-Body Irradiation

Substances

  • Integrin alpha Chains
  • RNA, Messenger
  • Tenascin
  • integrin alpha9
  • Fluorouracil