Hedgehog signaling in tissue renewal and repair
The maintenance of adult organs requires robust mechanisms for tissue renewal, whose disruption can result in disease. Failure of tissue renewal can cause organ degeneration, whereas disrupted regulation of cell proliferation associated with renewal may result in malignant growth. With these ideas as a central focus, we are currently investigating the mechanisms that control postembryonic tissue renewal, and how these mechanisms are subverted in pathological states (see Hedgehog signaling in cancer).
Our previous investigations helped establish the principle of graded, concentration-dependent cellular responses as a central mechanism of embryonic tissue patterning by morphogenic signals. Tissue renewal in contrast does not operate within a field of primitive embryonic cells and instead depends on tissue-specific stem cells, which must function within the postnatal structure of an established organ. Stem cells do not, however, autonomously contain the spatiotemporal information required to effectively direct tissue renewal. Our recent work spanning several epithelial organs indicates that this information resides within nearby stromal cells that constitute the stem cell niche, producing signals that regulate stem and progenitor cell activities such as proliferation, differentiation, or the pattern of branching morphogenesis.
Select Reviews and Publications:
Tabula Muris Consortium; Single-cell transcriptomics of 20 mouse organs create a Tabula Muris. Nature, 562(7727): 367-372 (2018). Pubmed
Roberts, K.J., Kershner, A.M., Beachy, P.A. The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy. Cancer Cell, 32(4):404-410 (2017). Pubmed
Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W-J., Clarke, M.F., Beachy, P.A. Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. Science, 356(6335): eaal3485 (2017). Pubmed
Lim, A., Shin, K., Zhao, C., Kawano, S., Beachy, P.A. Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate. Nat Cell Biol. 16(12):1135-45 (2014). PMC4327780 Pubmed
Shin, K., Lee, J., Guo, N., Kim, J., Qu, L., Mysorekar, I., Beachy, P.A. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472:110-4 (2011). PMC3676169. Pubmed