Jeffrey A. Hubbell (PI)
University of Chicago
Morphogenetic signals from the cell’s microenvironment play important roles in stem and progenitor cell differentiation and in multicellular morphogenesis, being driven by extracellular matrix (ECM) proteins and cytokines. We focus on how signaling from cytokines is modulated by the presence of and interactions with ECM proteins and how this modulates morphogenesis. This interaction leads to synergistic signaling between adhesion receptors and cytokine receptors. We develop molecular engineering approaches to create recombinant cytokine variants that bind the ECM with unusually high affinity, to enhance their translational potential. Recombinant ECM proteins can be built into biomaterials, or they can be assembled into a gel network to be used as a biomaterial matrix themselves. Our goal is to use these matrix and cytokine engineering approaches to support the multicellular morphogenesis that occurs between nephron progenitor cells, the developing microvasculature, and other stromal cells.
Oxburgh, L; Carroll, TJ; Cleaver, O; Gossett, DR; Hoshizaki, DK; Hubbell, JA; Humphreys, BD; Jain, S; Jensen, J; Kaplan, DL; Kesselman, C; Ketchum, CJ; Little, MH; McMahon, AP; Shankland, SJ; Spence, JR; Valerius, MT; Wertheim, JA; Wessely, O; Zheng, Y; Drummond, IA. J Am Soc Nephrol. 28(5):1370–1378. May 2017.
(Re)Building a Kidney is a National Institute of Diabetes and Digestive and Kidney Diseases-led consortium to optimize approaches for the isolation, expansion, and differentiation of appropriate kidney cell types and the integration of these cells into complex structures that replicate human kidney function. The ultimate goals of the consortium are two-fold: to develop and implement strategies for in vitro engineering of replacement kidney tissue, and to devise strategies to stimulate regeneration of nephrons in situ to restore failing kidney function. Projects within the consortium will answer fundamental questions regarding human gene expression in the developing kidney, essential signaling crosstalk between distinct cell types of the developing kidney, how to derive the many cell types of the kidney through directed differentiation of human pluripotent stem cells, which bioengineering or scaffolding strategies have the most potential for kidney tissue formation, and basic parameters of the regenerative response to injury. As these projects progress, the consortium will incorporate systematic investigations in physiologic function of in vitro and in vivo differentiated kidney tissue, strategies for engraftment in experimental animals, and development of therapeutic approaches to activate innate reparative responses.