A Murine Model of Hepatic Veno-occlusive Disease Induced by Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Hepatic veno-occlusive disease (HVOD) is a life-threatening complication of bone marrow stem cell transplantation. The understanding of this clinical condition is hampered by the lack of suitable animal models. Here, we present a murine (BALB/c-based) model of HVOD induced by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The chimerism rate of bone marrow was measured on days 5 and 10, while the chimerism rate of peripheral blood was measured on day 15 after allo-HSCT. Percentages of peripheral reticulocytes and serum levels of bilirubin and alanine aminotransferase (as liver function tests) were measured on days 5, 10, 15, 20, and 30. Livers were obtained on days 5, 10, 15, 20, and 30, and fixed in formaldehyde or glutaric dialdehyde. Liver slices were processed using the hematoxylin-eosin, Masson's trichrome, or immunohistochemistry staining, and examined by light or transmission electron microscopy. Sinusoidal damages were the earliest pathological changes occurring in the allo-HSCT-induced HVOD, followed by coagulative necrosis of liver cells. The liver cell necrosis was later attenuated and sinusoidal endothelial cell morphology improved. However, on day 30, the edema and necrosis of liver cells became aggravated again. Furthermore, sinusoidal lining cell regeneration and partly attenuated liver cell necrosis were followed by the moderate to severe central vein fibrosis. In conclusion, we have successfully established a murine model of HSCT-HVOD. This model develops moderate to severe HVOD which cannot heal without intervention.

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

“…29 Efforts to establish a rodent model of SOS arising from hematopoietic stem cell transplantation also have more recently met with success, using an allogeneic transplantation model involving male C57BL/6 male mice as donors and female BALB/c mice preconditioned with whole body irradiation as recipients. 48 This gives further opportunity for productive future studies into the pathogenesis of SOS.…”

Treprostinil reduces endothelial damage in murine sinusoidal obstruction syndrome

“…We examined the action of treprostinil in a murine model of SOS, which relied on allo-HSCT in mice preconditioned by whole body irradiation [27]. Our approach was designed to detect a protective effect on the early insult to the sinusoidal endothelium.…”

“…Histological sections of the liver were surveyed to explore the reason for this discrepancy. The changes were scored (0 to 3 points/item) along seven dimensions [27]; the resulting quantification is shown in Fig. 4.…”

“…The murine model of SOS described by Zeng et al [27, 28] is based on an allogeneic hematopoietic stem cell transplantation (allo-HSCT), where preconditioning is achieved by whole body irradiation. In that model, the maximum of SOS is observed 15 days after allogeneic hematopoietic stem cell transplantation.…”

“…The primary outcome parameter was hepatomegaly, and the number of animals was based on the following assumptions: the liver-to-body weight ratio (liver weight as % of body weight) was to increase from a mean of 5.5% with a standard deviation of 0.5% to 7.5 ± 0.7% on day 15 [27]. This increase was to be halved by treprostinil.…”