Combined implantation of CD34+ and CD14+ cells increases neovascularization through amplified paracrine signalling

J Tissue Eng Regen Med. 2013 Feb;7(2):118-28. doi: 10.1002/term.503. Epub 2011 Nov 28.

Abstract

Cell therapy strategies that use adult peripheral blood-derived CD34⁺ progenitor cells are hampered by low cell numbers and the infrequent cellular incorporation into the neovasculature. Hence, the use of CD34⁺ cells to treat ischaemic diseases is under debate. Interaction between CD34⁺ cells and CD14⁺ cells results in superior endothelial differentiation of CD14⁺ cells in vitro, indicating that cell therapy approaches utilizing both CD34⁺ and CD14⁺ cells may be advantageous in therapeutic neovascularization. Here, human CD34⁺ and CD14⁺ cells were isolated from adult peripheral blood and implanted subcutaneously into nude mice, using matrigel as the carrier. Combined implantation of human CD34⁺ and CD14⁺ cells resulted in superior neovascularization, compared to either cell type alone, albeit incorporation of human cells into the murine vasculature was not observed. Human CD34⁺ and CD14⁺ cells produced and secreted a pentad of pro-angiogenic mediators, such as HGF, MCP-1 and IL-8, bFGF and VEGFa in monoculture. The production and secretion of pro-angiogenic mediators by CD14⁺ cells was highly amplified upon incubation with conditioned medium from CD34⁺ cells. In vivo, neovascularization of matrigel implants did not rely on the endothelial differentiation and incorporation of CD34⁺ or CD14⁺ cells, but depended on the paracrine effects of IL-8, MCP-1, HGF, bFGF and VEGFa secreted by implanted cells. Administration of this growth factor/cytokine pentad using matrigel as a carrier results in cell recruitment and microvessel formation equal to progenitor cell-induced neovascularization. These data provide new insights on neovascularization by cell therapy and may contribute to new strategies for the treatment of ischaemic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism*
  • Cell Transplantation*
  • Collagen / pharmacology
  • Drug Combinations
  • Humans
  • Laminin / pharmacology
  • Lipopolysaccharide Receptors / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Physiologic* / drug effects
  • Paracrine Communication* / drug effects
  • Proteoglycans / pharmacology

Substances

  • Antigens, CD34
  • Drug Combinations
  • Laminin
  • Lipopolysaccharide Receptors
  • Proteoglycans
  • matrigel
  • Collagen