Our proposal addresses some of the solutions to the development of complex 3- dimensional tissue models and a new paradigm by using lymph node as in vivo bioreactors to grow tissue or organ substitute. Our initial study and prove of concept will be centered around the generation of ectopic liver in lymph nodes for patients suffering end-stage liver diseases. Hepatocyte transplantation has been reported as a possible therapeutic approach for liver disease. However, transplantation has been directed at the liver itself, limiting efficacy in patients with end-stage liver diseases, when cirrhosis and fibrosis are common. In this proposal we demonstrate that the generation of an ectopic liver within lymph nodes is an efficient method to restore hepatic function, highlighting the novel use of this organ as a site for hepatocyte transplantation. Homeostatic expansion of donor hepatocytes in lymph nodes resulted in the rescue of lethal hepatic failure. These data provide the first definitive evidence that a functional ectopic liver can rescue lethal hepatic diseases. Furthermore, with the efficacy of this approach suggests that lymph nodes have therapeutic potential for cell-based transplantation and tissue engineering. Our new paradigm to generate functional liver tissues in lymph nodes will be further applied to other tissues.

Public Health Relevance

Our proposal addresses some of the hurdles confronting the development of complex 3-D tissue models, and provides a new paradigm for tissue modeling, by using lymph nodes as in vivo bioreactors to grow tissue or organ substitutes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085711-05
Application #
8528566
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Serrano, Jose
Project Start
2009-09-25
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$664,918
Indirect Cost
$226,028
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Francipane, Maria Giovanna; Lagasse, Eric (2016) Regenerating a kidney in a lymph node. Pediatr Nephrol 31:1553-60
Cramer, Julie M; Thompson, Timothy; Geskin, Albert et al. (2015) Distinct human stem cell populations in small and large intestine. PLoS One 10:e0118792
Manohar, Rohan; Li, Yaming; Fohrer, Helene et al. (2015) Identification of a candidate stem cell in human gallbladder. Stem Cell Res 14:258-69
Francipane, Maria Giovanna; Lagasse, Eric (2015) The lymph node as a new site for kidney organogenesis. Stem Cells Transl Med 4:295-307
Francipane, Maria Giovanna; Lagasse, Eric (2014) Maturation of embryonic tissues in a lymph node: a new approach for bioengineering complex organs. Organogenesis 10:323-31
DeWard, Aaron D; Komori, Junji; Lagasse, Eric (2014) Ectopic transplantation sites for cell-based therapy. Curr Opin Organ Transplant 19:169-74
Komori, Junji; DeWard, Aaron D; Gramignoli, Roberto et al. (2014) Potential barriers to human hepatocyte transplantation in MUP-uPAtg(⁺/⁺)Rag2⁻/⁻γC⁻/⁻ mice. Cell Transplant 23:1537-44
DeWard, Aaron D; Cramer, Julie; Lagasse, Eric (2014) Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep 9:701-11
Cramer, Julie M; Zimmerman, Mark W; Thompson, Tim et al. (2014) Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice. Stem Cell Res 13:164-71
Song, X; Kim, S-Y; Zhou, Z et al. (2013) Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells. Cell Death Dis 4:e577

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