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Title: Epimorphic regeneration approach to tissue replacement in adult mammals

item AGRAWAL, VINEET - University Of Pittsburgh
item JOHNSON, SCOTT - University Of Pittsburgh
item REING, JANET - University Of Pittsburgh
item ZHANG, LI - University Of Pittsburgh
item TOTTEY, STEPHEN - University Of Pittsburgh
item WANG, GANG - Weill Medical College - Cornell
item HIRSCHI, KAREN - Children'S Nutrition Research Center (CNRC)
item BRAUNHUT, SUSAN - University Of Massachusetts
item GUDAS, LORRAINE - Weill Medical College - Cornell
item BADYLAK, STEPHEN - University Of Pittsburgh

Submitted to: Proceedings of the National Academy of Sciences(PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/27/2009
Publication Date: 2/23/2010
Citation: Agrawal, V., Johnson, S.A., Reing, J., Zhang, L., Tottey, S., Wang, G., Hirschi, K.K., Braunhut, S., Gudas, L.J., Badylak, S.F. 2010. Epimorphic regeneration approach to tissue replacement in adult mammals. Proceedings of the National Academy of Sciences. 107(8):3351-3355.

Interpretive Summary: In these studies, we tested the ability of extracellular matrix proteins, which were derived from decellularizing small intestine and bladder tissues, to promote vascularization and tissue repair in a model of limb regeneration. We found that the matrix proteins encouraged other cells within the tissue to grow and form new tissue to replace what was removed experimentally.

Technical Abstract: Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.