Shortly after the discovery of endothelial progenitor cells (EPCs) in 1997, many clinical trials were conducted using EPCs as a cellular based therapy with the goal of restoring damaged organ function by inducing growth of new blood vessels (angiogenesis). Results were disappointing, largely because the cellular and molecular mechanisms of EPC-induced angiogenesis were not clearly understood. Following injection, EPCs must migrate to the target tissue and engraft prior to induction of angiogenesis. In this study EPC migration was investigated in response to tumor necrosis factor α (TNFα), a pro-inflammatory cytokine, to test the hypothesis that organ damage observed in ischemic diseases induces an inflammatory signal that is important for EPC homing. In this study, EPC migration and incorporation were modeled in vitro using a coculture assay where TNFα treated EPCs were tracked while migrating toward vessel-like structures. It was found that TNFα treatment of EPCs increased migration and incorporation into vessel-like structures. Using a combination of genomic and proteomic approaches, NF-kB mediated upregulation of CADM1 was identified as a mechanism of TNFα induced migration. Inhibition of NF-kB or CADM1 significantly decreased migration of EPCs in vitro suggesting a role for TNFα signaling in EPC homing during tissue repair. Stem Cells 2016;34:1922–1933.
Bibliographical noteFunding Information:
We would like to thank S.Z.P. for her help with manuscript preparation. This work was supported by NIH Grant HL082798 and a gift from the Kern Family Foundation. A.P. was supported in part by an MSTP Institutional Training Fellowship from NIGMS (T32 GM80202). B.H. was supported by HL94273, DK105043, and MCW RAC award funding. C.C.K. was supported by K99/00-AG-039511.
© 2016 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
- Cellular migration
- Endothelial progenitor cells