Grant Award Details
Preclinical development of human hepatocyte progenitor cells for cell therapy
Determine if human hepatocyte progenitor cells, which exist in the normal adult liver, can be maintained and expanded in vitro while maintaining in vivo regenerative capacity.; expected outcome is a liver-derived, ex vivo expandable human hepatocyte progenitor cell population (HPCs) for treating liver damage/disease
<p>The overall goal of this project was to establish a stable, expandable source of hepatocytes for use in cell transplantation therapy for liver disease. The specific goal was to determine if human hepatocyte progenitor cells (HPCs), which exist in the normal adult liver, can be maintained and expanded <em>in vitro </em>while maintaining regenerative capacity after transplantation.</p><p>The work was based on earlier findings that HPCs exist in the mouse liver. With this CIRM award, we identified human counterparts of HPCs through gene expression studies and demonstrated both their <em>in vitro </em>proliferative capacity and <em>in vivo </em>regenerative capacity. We successfully established a robust cell culture system to propagate HPCs, isolated from cadaveric human hepatocytes samples, over many passages while maintaining the proliferative status of the cells. We achieved growth rates that would theoretically support the generation of billions of dividing HPCs, with ample proliferative capacity. These expanded cells maintained a gene expression profile similar to endogenous HPCs. </p><p>We succeeded in engrafting cultured human HPCs in a mouse liver injury model, although the efficiency of engraftment was lower than the mouse HPCs. We found that the engrafted and repopulating human HPCs have hallmarks of differentiation without evidence of tumor formation. </p><p>We continue to study further factors contributing to adult human HPC engraftment and regeneration following expansion. Thus, under this CIRM award, we developed a solid foundation to support ongoing patient-specific cell therapy-based approaches to liver diseases.</p>
Grant Application Details
- Preclinical development of human hepatocyte progenitor cells for cell therapy
Determine if human hepatocyte progenitor cells, which exist in the normal adult liver, can be maintained and expanded in vitro while maintaining in vivo regenerative capacity.
Cell transplantation therapy can be an effective alternative treatment for severe liver diseases to liver transplantation, which is severely limited by the lack of available donor organs.
Major Proposed Activities
- Characterize human pericentral hepatocytes and their niche in normal adult human liver
- Determine if human pericentral hepatocytes function as progenitor cells in a humanized mouse liver model
- Compare the regenerative capacity of human HPCs with mature hepatocytes
- Determine the optimum in vitro conditions for maintaining and expanding human HPCs
- Examine whether endothelial cells promote in vitro expansion of human HPCs
- Assess the liver repopulating capability of long-term culture expanded HPCs
Statement of Benefit to California:
Cellular therapy for severe liver disease in the form of hepatocyte transplantation is effective alternative to whole organ transplantation. However, its usage is limited by the severe shortage of healthy primary human hepatocytes. The potential to generate patient-specific sources of hepatocytes from HPCs for cellular therapy would address an immense unmet clinical need.
Source URL: https://www.cirm.ca.gov/our-progress/awards/preclinical-development-human-hepatocyte-progenitor-cells-cell-therapy