Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration

  title={Functional Modulation of ES-Derived Hepatocyte Lineage Cells via Substrate Compliance Alteration},
  author={Lulu Li and Nripen S. Sharma and Uday Chippada and Xue Jiang and Rene R Schloss and Martin L. Yarmush and Noshir A. Langrana},
  journal={Annals of Biomedical Engineering},
Pluripotent embryonic stem cells represent a promising renewable cell source to generate a variety of differentiated cell types including hepatocyte lineage cells, and may ultimately be incorporated into extracorporeal bioartificial liver devices and cell replacement therapies. Recently, we and others have utilized sodium butyrate to directly differentiate hepatocyte-like cells from murine embryonic stem cells cultured in a monolayer configuration. However, to incorporate stem cell technology… 
Neural lineage differentiation of embryonic stem cells within alginate microbeads.
Differentiation of embryonic stem cells into neural lineages in an alginate encapsulation microenvironment
A murine embryonic stem cell alginate-poly-l-lysine microencapsulation differentiation system is established that maintains cell viability, is conducive to ES cell differentiation to hepatocyte lineage cells, and sustains differentiated cellular function.
Generation of functional hepatocytes from mouse induced pluripotent stem cells
The results indicate that mouse induced pluripotent stem cells can efficiently differentiate into functional hepatocytes in vitro, which may be helpful for the study of liver development and regenerative medicine.
In Vitro Differentiation of Embryonic and Adult Stem Cells into Hepatocytes: State of the Art
This review focuses on current strategies to differentiate embryonic, mesenchymal(‐like), and liver stem/progenitor cells into hepatocytes in vitro, and some recommendations are proposed to standardize, optimize, and enrich the in vitro production of hepatocyte‐like cells out of stem/ ProGenitor cells.
Effect of substrate stiffness on early human embryonic stem cell differentiation
The utility of PDMS substrates for stem cell propagation and substrate mediated differentiation is evaluated with results indicating that these substrate systems could potentially be used to direct hESC fate towards early mesodermal lineages.
Effects of reconstituted collagen matrix on fates of mouse embryonic stem cells before and after induction for chondrogenic differentiation.
Investigation of the effects of reconstituted 3D collagen matrix on the fates of mouse ES cells before and after induction for chondrogenic differentiation suggests the inductive role of collagen matrix in differentiating mES cells toward mesenchymal lineages.
Substrate stiffness affects early differentiation events in embryonic stem cells.
A fundamental role for mechanosensing in mammalian development is suggested and the mechanical environment should be taken into consideration when engineering implantable scaffolds or when producing therapeutically relevant cell populations in vitro is illustrated.
Generation of functional hepatic cells from pluripotent stem cells.
An updated summary of hepatic differentiation protocols published so far is provided, with a characterization of the hepatic cells generated in vitro and their ability to regenerate damaged livers in vivo following transplantation in pre-clinical liver deficient mouse models.
Encapsulated mesenchymal stromal cells for in vivo transplantation
The combined findings support the inclusion of immobilized hMSC in post‐CNS trauma tissue protective therapy, and suggest that conversion of macrophages to the M2 subset is responsible, at least in part, for tissue protection.


Sodium butyrate‐treated embryonic stem cells yield hepatocyte‐like cells expressing a glycolytic phenotype
It is shown that Na‐butyrate‐mediated differentiated cells mediate energy metabolism predominantly through glycolysis and this metabolic and mitochondrial characterization can assist in evaluating stem cell differentiation and may prove useful in identifying key regulatory molecules in mediating further differentiation.
Generation of Hepatocyte-Like Cells from Human Embryonic Stem Cells
It is reported here that hES cells can be induced to differentiate into hepatocyte-like cells, and these cells may provide a reliable source of normal human hepatocytes for research and transplantation.
Engineering hepatocyte functional fate through growth factor dynamics: the role of cell morphologic priming.
Insight into the ability of cell shape to "prime" hepatocyte behavior in dynamic microenvironments were elucidated and the possibility of uncoupling and, thus, selectively manipulating, the concerted contributions of GF-induced cellular activation and substrate- and GF- induced cell morphogenesis toward induction of cell function was reported.
Embryoid body-mediated differentiation of mouse embryonic stem cells along a hepatocyte lineage: insights from gene expression profiles.
The results of these studies suggest that spontaneous and collagen-mediated differentiation induce cells with the highest levels of ALB expression but mature liver specific genes were only expressed in the spontaneous condition.
Liver stem cells: prospects for treatment of inherited and acquired liver diseases
  • N. Theise
  • Medicine, Biology
    Expert opinion on biological therapy
  • 2003
The current understanding of these various cell populations is summarized, and possible approaches to their therapeutic use are reviewed, including cell transplantation, bioartificial liver devices (BLDs), gene therapy and administration of exogenous factors to stimulate normal physiological responses to repair.
Mechanochemical manipulation of hepatocyte aggregation can selectively induce or repress liver-specific function.
These studies highlight a novel interplay of physicochemical parameters of the culture microenvironment, leading to selective enhancement or repression of differentiated functions of hepatocytes, in concert with the activation of cellular morphogenesis.
Stem cell therapy of the liver— Fusion or fiction?
  • M. Dahlke, F. Popp, S. Larsen, H. Schlitt, J. Rasko
  • Biology, Medicine
    Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
  • 2004
This review provides an overview of different stem cell populations in distinct models of liver regeneration aimed at unifying diverse views of liver stem cell biology and seeks to clarify the nomenclature of putative liver stem Cell types.
The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology
It is concluded that the ECM can stimulate cell differentiation by selectively activating transcriptional regulatory factors and that such regulation occurs coordinately with ECM-promoted changes in cell shape.