Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion

Abstract

Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs) Schwartz et al 1 demonstrated that multipotent adult progenitor cells (MAPCs) 2,3 from the bone marrow of humans as well as mice and rats, when cultured with fibroblast growth factor-4 (FGF-4) and hepatocyte growth factor (HGF) in matrigel, secreted albumin, expressed P450, took up low-density lipoprotein (LDL), and stored glycogen. 3 Lee et al reported that mesenchymal stem cells (MSCs) from human bone marrow and umbilical cord blood differentiated into hepatocyte-like cells with the use of HGF and oncostatin M. 4,5 Most recently, Jang et al reported that hematopoietic stem cells (HSCs) from mice devoid of progenitors and selected for unique properties displayed a plasticity by which they became liver cells when cocultured with injured liver separated by a barrier. 6 Thus, the origin of cells which may undergo hepatic differentiation as revealed by in vitro experiments were quite diverse, reflecting the sources, human or rodent, and methods of isolation.,The differentiation of bone marrow or umbilical cord blood derived cells into hepatocytes has also been demonstrated by in vivo transplantation procedures. In most of these transplantation studies, either isolated 7-12 or clonally defined [13][14][15][16][17][18][19][20][21] HSCs of donor origin, though their characteristics were not equally specified in each study, were found to induce hepatocytes in recipient liver, suggesting the differentiation potency of HSCs.However, in these studies HSCs were generally introduced intravenously and were surmised to reside once in bone marrow where they may undergo proliferation and differentiation. Therefore, the cells distributed to the liver via bone marrow may not necessarily represent the original HSCs themselves.In fact, some recent studies have disclosed that hepatocytes with apparent donor characters were the result of fusion of donor myelomonocytic cells differentiated from HSCs with host hepatocytes. 20,22 Further, the results of these studies with HSCs do not exclude the possibility that other cell types in bone marrow such as MSCs are also capable of undergoing hepatic differentiation. Thus, issues still remained to be clarified as to which cellular component of bone marrow is most suitable to bring about hepatic regeneration in consideration of future clinical application. It also remains to be solved if any bone marrow components indeed differentiate in vivo without fusion.In the present investigation, we attempted to examine the differentiation ability of fractionated human bone marrow components-MSCs, CD34 ϩ cells, and non-MSCs/CD34 Ϫ cells-into hepatocytes in vivo ...

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

“…A study reported that 2.5%–5% is necessary for reversing the liver injuries 59. We also observed additional CM‐Dil + /ALB + cells in the GF‐PEI‐MSN complex group; however, low amounts of these cells could not significantly reverse the injured liver, which was mentioned by previous investigators 60. One explanation for this low differentiation level may be that limited space is available for the donor cells to integrate into the CCl 4 ‐treated mouse,61 and they do so with low efficiency.…”

Adult stem cells in progression and therapy of hepatocellular carcinoma

“…Nevertheless, when human BM stem cell fractions were directly xenografted into rat liver damaged with allyl alcohol, only the fraction of MSCs developed into hepatocyte-like cells, positive for mRNA albumin expression. 42 These findings are supported and built up by Aurich et al, 37 who could show the functional integration of hepatocytes derived from BM MSCs into mouse livers. For this purpose the MSCs were preconditioned in vitro resulting in storage of glycogen, synthesis of urea and activation of hepatocyte-specific gene promoter of phosphoenolypyruvate carboxykinase (PCK1).…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…In animal models, the most promising cells for therapy appear to be mesenchymal stem cells (MSCs). If human MSCs are xenografted to the allyl alcohol-damaged livers of immunosuppressed rats, large groups of human albumin-positive hepatocytes are generated without cell fusion being involved [105]. Transplanted human MSCs also contribute to the hepatocyte mass, predominantly periportally, in the partially hepatectomized livers of immunodeficient mice when regeneration is impeded by a β-receptor antagonist [106].…”