Bone Marrow Cell Transplant does Not Prevent or Reverse Murine Liver Cirrhosis

Abstract

We tested the effect of bone marrow cell (BMC) transplantation in either preventing or reversing cirrhosis on an experimental model of chronic liver disease. Female Wistar rats were fed a liquid alcohol diet and received intraperitoneal injections of carbon tetrachloride (CCl 4 ) over 15 weeks. Ten animals (cell-treated group) received five injections of BMCs during the cirrhosis induction protocol (on the 4th, 6th, 8th, 10th, and 12th weeks) and four animals received the cells after liver injury was established through tail vein. Nine animals (nontreated group) were submitted to the previously described protocols; however, they received vehicle injections. Analyses were performed to verify whether the infusion of cells was effective in preventing the development of cirrhosis in our model of induction, and if the cells could reverse cirrhosis once it was established. Hepatic architecture and fibrotic septa were analyzed in liver slices stained with hematoxilin & eosin and Sirius red, respectively. Fibrosis quantification was measured by Sirius red histomorphometry. Indirect immunofluorescence was performed to detect the amount of tissue transglutaminase 2. Blood analyses were performed to assess liver injury and function by the assessment of alanine aminotransferase and albumin. Ultrasound was performed to analyze the portal vein caliber and presence of ascitis. Cirrhosis features (regenerative nodules and fibrous septa) were observed in histopathology after 15 weeks of continuous hepatic injury in nontreated and cell-treated groups. Collagen content, immunofluorescence analysis, and biochemical and ultrasound parameters were similar in nontreated and cell-treated groups; however, both groups showed significant differences compared to a normal control group. Cell infusions with bone marrowderived cells seem to be ineffective in improving morphofunctional parameters of the liver when applied to chronic cases either during or after establishment of the hepatic lesion.Key words: Cirrhosis; Bone marrow cell; Biochemistry; Histology; Ultrasound INTRODUCTIONfore, the study of alternative therapies, such as stem cell transplantation, becomes of utmost importance. Most studies performed with cell therapies in liver Liver cirrhosis is a worldwide prevalent disease that has serious impacts on public health issues. It derives diseases have been restricted to the therapeutic potential of these cells after a single cell infusion in animals with from chronic injury to the liver that is commonly caused by viral hepatitis and alcoholism (1,47,48).an already damaged liver (13,39,51). Nonetheless, liver diseases usually have a chronic course, developing over Despite great regenerative capacity of the liver, successive injuries result in a significant loss of hepatocytes many years before cirrhosis is discovered. Frequently, this evolution cannot be easily arrested because there is and excessive deposition of extracellular matrix components, leading to irreversible impairment of organ funcstill no cure available for diseases such ...

Early Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke

“…Bone marrow blood was aspirated under local anesthesia from both iliac crests and processed to isolate the mononuclear cell fraction. A total of 5ϫ10 8 BMMCs was suspended into a volume of 10 mL, and 1 mL of the cell suspension was radiolabeled with 99m Tc (radioactivity 111 MBq, physical half-life 6 hours), as described previously, 1,2 and then added back to the unlabeled cell suspension. After catheter navigation via femoral artery access under local anesthesia and conscious sedation, cells were injected into the M1 portion of the MCA, and the infusion was completed within Ϸ10 minutes.…”

Cirrhosis Model That Tracks Umbilical Cord Mesenchymal Cell Transplantation Using Liver Serum Parameters: A Pilot Study

“…Taken together, the histological and macroscopic features of the liver, mortality rates, and gene expression data support the association of serum parameters with progression of cirrhosis in the present rodent model. Studies carried out in chronic liver disease models have produced controversial results, with positive results in some studies [22] , but not in others [10,23] . These studies tried to establish adequate follow up protocols and some measured serum parameters of liver function, but only at the endpoint.…”

“…One of the studies using syngeneic bone marrow MSC in CCl4 induced chronic disease did measure albumin and ALT to assess liver function but also noticed that after a few weeks parameters improved regardless of treatment with MSC [10] . Finally, we chose to evaluate the results one week after treatment as MSC reportedly do not survive longer after injection into immunocompetent animals [23] , and therefore should be able to exert their effect in this narrow timeframe.…”

“…The more chronic disease models rely on the use of highly toxic drugs such as carbon tetrachloride (CCl4), thioacetamide and dimethylnitrosamine (DMN) [7,8] . In addition to very high mortality rates CCl4 induced damage is reversible when treatment is interrupted, a limiting factor in studies where an extended therapeutic window is desirable [9,10] . In the case of TAA, a very long treatment period is needed to achieve significant fibrosis [11] .…”

Therapeutic Strategies of Stem Cell Transplantation for Liver Cirrhosis

“…Consequently, the resulting anti-inflammatory effect is less than that seen with MSCs. Experiments using a rat model of severe cirrhosis showed that liver fibrosis was exacerbated by BMNCs transplantation, but was ameliorated by BMSCs transplantation [57] [58] [59]. Similarly, it was demonstrated by the animal experiments that BMSCs had better therapeutic effect on acute liver injury with the respects to anti-inflammation and anti-fibrosis activity [60].…”