Pancreas and Kidney Transplantation Using Embryonic Donor Organs

Abstract

One novel solution to the shortage of human organs available for transplantation envisions 'growing' new organs in situ. This can be accomplished by transplantation of developing organ anlagen/primordia. We and others have shown that renal anlagen (metanephroi) transplanted into animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro prior to transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Similarly, pancreatic anlagen can be transplanted across concordant and highly disparate barriers, and undergo growth, differentiation and secrete insulin in a physiological manner following intra-peritoneal placement. Implantation of the embryonic pancreas, is followed by selective differentiation of islet components. Here we review studies exploring the potential therapeutic applicability for organogenesis of the kidney or endocrine pancreas.

Development of a novel xenotransplantation strategy for treatment of diabetes mellitus in rat hosts and translation to non-human primates

“…of agents that are not approved for human use or that result in a high level of morbidity and mortality. 1,4,[6][7][8] As reviewed previously in Organogenesis, [6][7][8] the use of embryonic tissue (kidney or pancreas) for transplantation offers theoretical advantages relative to transplantation of either stem cells or adult differentiated Photographs of mesentery from a rat (A and B) or a rhesus macaque (C and D) several weeks following sham-transplantation (A) or transplantation of E28 pig pancreatic primordia (B) or immediately following the transplantation of an E28 pig pancreatic primordium (C, arrowhead) or several weeks following transplantation (D). Arrow, lymph node (D).…”

“…The studies reviewed above represent one of two independent decade-long efforts (ours based at Washington University [6][7][8] and the other at the Weizmann Institute of Science, Rehovot Israel 17,18 ) to adapt xenotransplantation of embryonic pig pancreas as a novel therapy for diabetes mellitus in humans. Hecht et al 17 (Weizmann Institute) applied findings generated in mice (Tchorsh-Yutsis et al) 18 to a non-human primate model.…”

Maturation of nephrons by implanting hPSC-derived kidney progenitors under kidney capsules of unilaterally nephrectomized mice

“…Mouse metanephric tissue transplantation was performed as previously described [15,16]. Upon implantation under the renal capsule of recipient immune-compromised single-nephrectomized mice, organoid maturation degree was evaluated.…”

Organogenetic tolerance

“…The severity of humoral rejection due to preexisting natural antibodies effectively precludes the use of non-transgenic swine as whole organ (pancreas) donors in primate hosts. [1][2][3][4][5][6][7][8][9] However, isolated cells such as islets of Langerhans (islets) can be transplanted into humans 6 or non-human primates 7,8 without initiating humoral rejection. Recent experience with pig to primate islet, 7 neonatal islet, 8 or hCD46 transgenic pig islet 9 transplantation shows that sustained insulin independence can be achieved, but unfortunately only through the use of immune suppressive agents that are not approved for humans or would result in an unacceptable level of morbidity.…”