Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers

Abstract

Aims: At present, clinical success of hepatocyte transplantation as an alternative to whole liver transplantation is hampered by the limited availability of suitable donor organs for the isolation of transplantable hepatocytes. Hence, novel cell sources are required to deliver hepatocytes of adequate quality for clinical use. Mesenchymal stem cells (MSCs) from human bone marrow may have the potential to differentiate into hepatocytes in vitro and in vivo. Methods: Isolated MSCs were selected by density gradient centrifugation and plastic adherence, differentiated in the presence of human hepatocyte growth medium and transplanted in immunodeficient Pfp/Rag2 mice. Results: Here, we demonstrate that human MSCs gain in vitro the characteristic morphology and function of hepatocytes in response to specified growth factors. Specifically, preconditioned MSCs store glycogen, synthesise urea and feature the active hepatocyte-specific gene promoter of phosphoenolpyruvate carboxykinase (PCK1). After transplantation into livers of immunodeficient mice, preconditioned MSCs engraft predominantly in the periportal portion of the liver lobule. In situ, the cells continue to store glycogen and express PCK1, connexin32, albumin and the human hepatocyte-specific antigen HepPar1, indicating that the transplanted cells retain prominent qualities of hepatocytes after their regional integration. Conclusion: MSCs derived from human bone marrow may serve as a novel source for the propagation of hepatocyte-like cells suitable for cell therapy in liver diseases.

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

“…First, ESCs could generate functional hepatocytes in vivo that are then engrafted efficiently within the host liver 6. 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.…”

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

“…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]. Human MSCs from adipose tissue, selected on the basis of CD105 (endoglin) expression, also generate hepatocytes when injected into nude mice at 24 h after CCl 4 injury [107].…”

Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration

“…Recently, many studies have been conducted to investigate the hepatocyte differentiation properties of MSCs in response to various culture conditions. 6,7,28 Potential candidates include hepatocyte growth factor, epidermal growth factor, oncostatin M, and vascular endothelial growth factor, and these factors were therefore nominated as modulators of stem cell differentiation. 5,[29][30][31] However, the length of time required during hepatic differentiation of MSCs under prolonged exposure in the specific culture media is the major drawback.…”

“…1,2 A number of reports have suggested that MSCs from rat, mouse, and human can be induced to differentiate into functional hepatocyte-like cells and express certain distinct hepatocyte markers and provide functional support. [3][4][5][6][7] Although the capability of MSCs to differentiate into hepatocytes has been established, the precise underlying mechanism that regulates the differentiation process is still unclear.…”