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A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells

Abstract

Tissue injury may create a specific microenvironment for inducing the systemic participation of stromal-like cells in the repair process. Here we show that substance P is an injury-inducible factor that acts early in the wound healing process to induce CD29+ stromal-like cell mobilization. Likewise, mobilization of such cells also occurs in uninjured mice, rats and rabbits if substance P is intravenously injected. Upon further characterization these substance P–mobilized CD29+ cells were found to be similar to stromal cells from a number of connective tissues, including bone marrow (that is, bone marrow stromal cells, or BMSCs). Both substance P injection and transfusion of autologously derived substance P–mobilized CD29+ cells from uninjured rabbits accelerated wound healing in an alkali burn model. Also, epithelial engraftment of the transfused cells into the injured tissue occurred during the wound healing. Finally, using human BMSCs as a test population, we show that substance P stimulates transmigration, cell proliferation, activation of the extracellular signal–related kinases (Erk) 1 and 2 and nuclear translocation of β-catenin in vitro. This finding highlights a previously undescribed function of substance P as a systemically acting messenger of injury and a mobilizer of CD29+ stromal-like cells to participate in wound healing.

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Figure 1: Substance P (SP) is an injury-inducible factor and a mobilizer of CD11bCD29+CD90+CD105+CD106+ cells.
Figure 2: Substance P kinetics, modulated either by wound size or by substance P injection, determines the mobilization of CD29+ cells showing multipotent differentiation capacities.
Figure 3: Injection of substance P just after injury accelerates wound healing and mobilization of CD29+ cells.
Figure 4: Transfusion of autologous substance P–mobilized CD29+ stromal-like cells (SP-SLC) accelerates wound healing, and the cells are engrafted in injured tissue, preferentially in the epithelial layer.
Figure 5: Transmigration of human BMSCs on a three-dimensional collagen gel is accompanied by concomitant induction of MMPs and inhibition of TIMPs.
Figure 6: Substance P stimulates cell proliferation, Erk1/2 activation and nuclear translocation of β-catenin in human BMSCs.

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Acknowledgements

We gratefully acknowledge the support of a grant (SC3120) from the Stem Cell Research Center of the 21st Century Frontier Research Program of the Korea Ministry of Education, Science and Technology; a Musculoskeletal Bioorgan Center grant from the Korea Ministry of Health and Welfare (A040003) and a grant of Atomic Research and Development fund from the Ministry of Education, Science and Technology, given to Y.S. We would like to thank P. Robey at the US National Institute of Dental & Craniofacial Research for providing HA-TCP particles and protocols for ectopic bone formation.

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H.S.H., J.C.K. and Y.S. conceived the idea; H.S.H. and Y.S. designed the experiments, interpreted the data and wrote the paper; H.S.H., J.L., E.A.L., Y.S.K., E.L., W.A. and M.H.J. performed the experiments.

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Correspondence to Jae Chan Kim or Youngsook Son.

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Hong, H., Lee, J., Lee, E. et al. A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells. Nat Med 15, 425–435 (2009). https://doi.org/10.1038/nm.1909

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