Walter S. and Lucienne Driskill
Graduate Training Program in Life Sciences

DGP Northwestern

Jason Wertheim

Jason Wertheim, MD, PhD Assistant Professor, Surgery Organ regeneration and tissue engineering E-mail:   jwerthei@nmh.org

The major area of interest in my laboratory is advancing the state of art in organ regeneration and tissue engineering to develop methods to grow livers, kidneys and hearts as a cutting-edge solution to the organ shortage dilemma. Nationally over 112,000 patients are waiting for solid organ transplantation, yet the number of transplants performed annually falls short of this need by 75%. In the absence of suitable donors for solid organ transplantation, organ failure leads to associated health problems, increased health care expenditures and death.  Organ shortage is a national issue with local impact. In 2010 there were just over 1050 solitary kidney, liver, or heart transplants performed in Illinois yet 311 patients died in the state alone, and more than 6650 nation-wide, waiting for an organ.

Our research proposes a multidisciplinary solution to organ shortage by utilizing a tissue engineering approach to rehabilitate the extracellular matrix of organs that are not initially suitable for transplantation. Just-in-time organs, reconstituted with recipient derived progenitor cells, would abrogate the need for long waitlist times and associated waitlist mortality, reduce the reliance on organs from living donors, and obviate the need for immunosuppression. Conceptually, these organs would be prepared from a donor matrix using a recipients own cells at the first signs of organ dysfunction. The re-engineered organ would then be ready for implantation when progressive organ failure indicates the need for transplantation. 

The traditional paradigm in tissue engineering has been to grow cells on synthetic, polymer scaffolds to recreate the organ or tissue of interest. The limitation of this approach is the scale-up. Beyond a critical distance, diffusion of nutrients and oxygen is not sufficient to support cellular life, and a vascular system must be incorporated into the tissue to supply nutrients. It has been technically difficult to design a synthetic micro-vasculature resembling small, terminal capillaries and to combine these structures with functional cells. Our approach challenges this paradigm by using the natural extracellular matrix as a scaffold to support the growth of new cells capable of repopulating and habilitating a scarred organ. We have established protocols to remove parenchyma cells from livers, kidneys and hearts with high efficiency of cellular removal and adequate retention of extracellular matrix molecules. We have further repopulated the vasculature of these matrix structures with endothelial cells derived from induced pluripotent stem cell technology. Together, we have partnered with the McCormick School of Engineering at Northwestern University and other leading academic and industrial centers to advance this fast moving field and address the problem of organ shortage.

Publications:

Shah SS, Wertheim J, Wang CT, Pitt CG. “Polymer-drug conjugates: Manipulating drug delivery kinetics using model LCST systems.” Journal of Controlled Release. 45, 95-101 (1997).

Pitt CG, Wertheim J, Wang CT, Shah SS. “Polymer-drug conjugates: Manipulation of drug delivery kinetics.” Macromolecular Symposia. 123, 225-234 (1997).

He Y, Wertheim JA, Xu L, Miller JP, Karnell FG, Choi JK, Ren R, Pear WS. “The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.” Blood. 99, 2957-2968 (2002).

Janowska-Wieczorek A, Majka M, Marquez-Curtis L, Wertheim JA, Turner AR, Ratajczak MZ. “Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants.” Leukemia. 16, 1160-1166 (2002).

Wertheim JA, Forsythe K, Druker BJ, Hammer D, Boettiger D, Pear WS. “BCR-ABL induced adhesion defects are tyrosine kinase independent.” Blood. 99, 4122-4130 (2002).

Wertheim JA, Miller JP, Xu L, He Y, Pear WS. “The biology of chronic myelogenous leukemia: Mouse models and cell adhesion.” Oncogene. 21, 8612-8628 (2002).

Wertheim JA, Perera SA, Hammer DA, Ren R, Boettiger D, Pear WS. “Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development.” Blood. 102, 2220-2228 (2003).

Stewart CA, Wertheim J, Olthoff K, Furth EE, Brensinger C, Markman J, Shaked A. “Ascites after liver transplantation—a mystery.” Liver Transplantation. 10, 654-660 (2004).

Wertheim JA, Petrowsky H, Saab S, Kupiec-Weglinski JW, Busuttil RW. “Major Challenges Limiting Liver Transplantation in the United States.” American Journal of Transplantation. 11(9) 1773-1784 (2011).