Xenotransplantation of Human Umbilical Cord Blood Mononuclear Cells to Rats with D-Galactosamine-Induced Hepatitis

Abstract

Cord blood is an attractive cell source in regenerative medicine and represents an alternative to bone marrow. The aim of this study was to investigate whether human umbilical cord blood mononuclear (HUCBM) cells might be valuable in hepatic regenerative medicine. HUCBM cells differentiated in vitro into hepatocytes, as suggested by expression of albumin, cytokeratin-18, glutamine synthetase, α-fetoprotein, and cytochrome P450 3A4 at both mRNA and protein levels in a time-dependent fashion. In contrast, the hematopoietic phenotype was gradually lost, as demonstrated by disappearance of CD45 expression. The regenerative potential of HUCBM cells was tested by using a human-to-rat xenotransplant model in which HUCBM cells were intraportally injected into rats with D-galactosamine-induced hepatitis. Liver histology and biochemical markers of hepatic damage were determined. Presence of human cells was detected in blood and liver of both control and D-galactosamine-treated animals. Cell transplantation produced an improvement in both the histological damage and liver function, as demonstrated by plasma values of alkaline phosphatase, γ-glutamyl transferase, lactate dehydrogenase, and total and direct bilirubins. Results obtained suggest that HUCBM cells are capable of hepatic engraftment in this human-to-rat xenotransplant model and that transplantation of HUCBM cells may be a suitable therapy for liver disease.

Human Umbilical Cord Blood Cell Grafts for Brain Ischemia

“…The cells used for transplantation into humans are preferred to be of human origin. Although xenografting of human cells into the rodent is a widely accepted research paradigm that often yields promising results (1, 125), this presents a dilemma in in vivo research with human-originated stem cells. While hUCB cells show the inability to generate cytotoxic T cells that respond to allogenic antigens, and to produce the proinflammatory cytokines such as IFN-γ and TNF-α, transplantation of hUCB cells into adult or aged rat brains was associated with vigorous rejection and strong immunosuppression was required to protect the graft (126).…”

Deleterious Effect of Human Umbilical Cord Blood Mononuclear Cell Transplantation on Thioacetamide-Induced Chronic Liver Damage in Rats

“…Presence of human cells in the liver parenchyma of the rats was confirmed by flow cytometry, Western blot, and confocal microscopy. Flow cytometry results indicated that the number of human cells engrafted in the rat livers was higher in the present model of chronic liver disease than in the acute model (1), with a maximum fluorescence of 2.91% in the latter versus 4.62% in the former.…”

“…Cirrhotic and control animals underwent intraportal transplantation of HUCBM cells. Rejection of the human cells by the recipient rats was avoided with an immunosuppressive treatment based on cyclosporine A and an antibody that depletes natural killer lymphocytes, as previously validated in an acute model of liver disease in which animals received an injection of 2 × 10 6 HUCBM cells (1). In the present study we delivered a fivefold higher amount of cells to test whether the number of human cells that reached the liver could be increased.…”

“…With the exception of groups C and T, all animals (receiving water, TAA, injection of cells or culture medium, i.e., groups CS, CU, TS, and TU) were subjected to immunosuppressive therapy with both cyclosporin A and an anti-asialo GM1 antibody (1). Cyclosporin A was administered intramuscularly and daily starting the day before cell transplantation or sham operation, at a dose of 15 mg/kg.…”

“…Our research group investigates whether human mononuclear cells isolated from umbilical cord blood (HUCBM cells) might be valuable in hepatic regenerative medicine. We recently demonstrated that HUCBM cell transplantation improves histological alterations and function of the liver in rats with acute liver damage (1). In the present experimental study, we portally injected HUCBM cells into rats with hepatic cirrhosis induced by thioacetamide, an experimental model of chronic liver disease that generates an intense fibrosis and mimics the histological alterations found in the human disease (4,16).…”