Isolation of a Bone Marrow-Derived Stem Cell Line with High Proliferation Potential and Its Application for Preventing Acute Fatal Liver Failure

Abstract

Transplantation of hepatocytes or hepatocyte-like cells of extrahepatic origin is a promising strategy for treatment of acute and chronic liver failure. We examined possible utility of hepatocyte-like cells induced from bone marrow cells for such a purpose. Clonal cell lines were established from the bone marrow of two different rat strains. One of these cell lines, rBM25/S3 cells, grew rapidly (doubling time, ϳ24 hours) without any appreciable changes in cell properties for at least 300 population doubling levels over a period of 300 days, keeping normal diploid karyotype. The cells expressed CD29, CD44, CD49b, CD90, vimentin, and fibronectin but not CD45, indicating that they are of mesenchymal cell origin. When plated on Matrigel with hepatocyte growth factor and fibroblast growth factor-4, the cells efficiently differentiated into hepatocyte-like cells that expressed albumin, cytochrome P450 (CYP) 1A1, CYP1A2, glucose 6-phosphatase, tryptophane-2,3-dioxygenase, tyrosine aminotransferase, hepatocyte nuclear factor (HNF)1␣, and HNF4␣. Intrasplenic transplantation of the differentiated cells prevented fatal liver failure in 90%-hepatectomized rats. In conclusion, a clonal stem cell line derived from adult rat bone marrow could differentiate into hepatocyte-like cells, and transplantation of the differentiated cells could prevent fatal liver failure in 90%-hepatectomized rats. The present results indicate a promising strategy for treating human fatal liver diseases.

In vitro transdifferentiation of adult hematopoietic stem cells: An alternative source of engraftable hepatocytes

“…In the past few years, adult stem cells plasticity has increased the possibility of using stem cells of one organ to repair others. In this context, the function of BM-derived cells in regenerating damaged liver has been addressed by many investigators [7][8][9][10][11][12][13][14]. Although, the contribution of BMCs in liver regeneration is found to be low to moderate, its significance has been widely recognized.…”

“…Numerous in vivo studies in the recent past have indicated that adult hematopoietic stem cells (HSCs) differentiate into hepatocytes in rodents [7][8][9][10][11][12][13][14]. As shown by these investigators, either liver damage or a strong selection pressure is a prerequisite for such differentiation [7,8,[14][15][16][17].…”

Effects of Bone Marrow Mesenchymal Stem Cells on Cell Proliferation and Growth Factor Expression of Limbal Epithelial Cells in vitro

“…A few cells stained positive for CD45 (1.16%), CD34 (7.90%) or CD11b (1.28%), whereas the majority of the cells stained positive for CD90 (99.78%) and CD29 (99.79%), which was in line with the cell surface marker features of MSCs (fig. 1) [19,20,21]. …”

Potential of Mesenchymal Stem Cells for Liver Regeneration

“…Based on these promising characteristics, MSC have now been tested in a wide variety of injury/disease model systems for their ability to generate hepatocytes and correct these liver defects. Using MSC isolated from a variety of mouse, rat, and human tissues, investigators have now provided evidence that MSC can mediate varying degrees of correction/repair of the liver following injury due to partial hepatectomy [126,[130][131][132][133], treatment with the toxin CCl4 [134][135][136][137][138][139][140][141][142][143][144][145], injury induced by allylalcohol [146,147], and treatment with 2-acetylaminofluorene [139].…”