Therapeutic Liver Reconstitution With Murine Cells Isolated Long After Death

Abstract

Background and Aims Due to the shortage of donor organs many patients needing liver transplantation cannot receive one. For some liver diseases hepatocyte transplantation could be a viable alternative, but donor cells are currently procured from the same sources as whole organs and thus the supply is severely limited. Methods Here, we investigated the possibility of isolating viable hepatocytes for liver cell therapy from the plentiful source of morgue cadavers. In order to determine the utility of this approach, cells were isolated from the livers of non-heart-beating cadaveric mice long after death and transplanted into fumarylacetoacetate hydrolase (Fah) deficient mice, a model for the human metabolic liver disease hereditary tyrosinemia type I and a stringent in vivo model for hepatic cell transplantation. Results Surprisingly, complete and therapeutic liver repopulation could be achieved with hepatocytes derived up to 27 hours post-mortem. Conclusions Competitive repopulation experiments demonstrated that cadaveric liver cells had a repopulation capacity similar to freshly isolated hepatocytes. Importantly, viable hepatocytes could also be efficiently isolated from cadaveric primate liver (monkey and human). These data provide evidence that non-heart-beating donors could be a suitable source of hepatocytes for much longer time periods than previously thought possible.

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

“…Significantly, post mortem skeletal muscle and HSCs maintain their functional properties in vitro and after transplantation, or after prolonged storage in anoxia. It is generally thought that stem cells lose their potential and utility for experimental and clinical purposes within 24-48 h post mortem in the necrotic environment of the cadaver, and several studies have reported that neural and HSCs can survive within this time interval [1][2][3][4]6,7,40 . Here we describe culture conditions that permit the survival of two stem cell types for remarkably longer periods post mortem than previously described, while retaining full engraftment potential.…”

“…Stem cells from post mortem tissues are currently used for experimentation, yet stem cell viability and regenerative capacity are thought to decline significantly in cadavers, consequently these studies have been limited to about 2 days after death [1][2][3][4][5][6][7] . Here we describe culture conditions that permit the survival and full engraftment potential of muscle and haematopoietic stem cells (HSCs) for remarkably longer periods post mortem than previously described, providing a source of stem cells for use in studying stem cell biology.…”

Cadaveric cardiosphere-derived cells can maintain regenerative capacity and improve the heart function of cardiomyopathy

“…3 Erker found hepatic cells isolated up to 27 hours post mortem could be effectively used for liver cell therapy. 4 Moreover, Hjelm et al demonstrated that cadaveric neuropheres were easier to obtain in early postnatal animals than in adult rats. 24 The isolation of viable and functional cadaveric stem cells from human bone marrow, brain, and muscle many days post mortem is possible today; but questions about cadaveric CDCs remained unsolved.…”

“…Cadaveric hepatocytes not only survived prolonged ischemia but also maintained their ability to engraft, repopulate, and correct metabolic liver disease in Fah¡/¡ mice. 4 In another study, a human cadaveric corneal endothelial button could be used to treat more than one cornea of patients with diseased endothelium. 30 We found that intramyocardial injection of 24 h-CDCs post mortem could not only reduce cardiac collagen content, but also improve cardiac function in vivo.…”

“…Mesenchymal stem cells (MSCs), skeletal muscle stem cells, and hepatic stem cells could be cultured from cadaveric organs and tissues while maintaining viability. [2][3][4] Successful isolation, propagation, functional characterization, and cryopreservation of human cadaveric MSCs derived from variously sized arterial segments 4 d post mortem have been maintained for more than 5 y. 2 Latilet et al 3 confirmed that viable and functional skeletal myogenic cells can be obtained from humans up to 17 days, and from mice up to 14 d post mortem.…”