Successful Transplantation of Human Hepatic Stem Cells with Restricted Localization to Liver Using Hyaluronan Grafts

Abstract

Cell therapies are potential alternatives to organ transplantation for liver failure or dysfunction but are compromised by inefficient engraftment, cell dispersal to ectopic sites, and emboli formation. Grafting strategies have been devised for transplantation of human hepatic stem cells (hHpSCs) embedded into a mix of soluble signals and extracellular matrix biomaterials (hyaluronans, type III collagen, laminin) found in stem cell niches. The hHpSCs maintain a stable stem cell phenotype under the graft conditions. The grafts were transplanted into the livers of immuno-compromised murine hosts with and without carbon tetrachloride treatment to assess the effects of quiescent versus injured liver conditions. Grafted cells remained localized to the livers resulting in a larger bolus of engrafted cells in the host livers under quiescent conditions and with potential for more rapid expansion under injured liver conditions. By contrast, transplantation by direct injection or via a vascular route resulted in inefficient engraftment and cell dispersal to ectopic sites. Transplantation by grafting is proposed as a preferred strategy for cell therapies for solid organs such as liver.

Tissue Engineering

“…After the STZ treatment the mice that had received transplanted human islet-like clusters indeed became significantly less hyperglycemic than controls that had not received cell therapy. The presence of functional b-like cells derived from the biliary tree stem cells was supported by detection of human C-peptide in the circulation, and its level was regulated correctly in response to a glucose challenge [499]. Thus, it appears that biliary tree stem cells, which could be harvested from tissue frequently discarded after certain surgical procedures and should also be accessible by laparoscopy, represent a potential cell source for tissue engineering of islet-like structures for diabetes therapy.…”

“…Excitingly, these stem cells also offer hope for engineering of pancreatic islet-like structures to treat insulin-dependent diabetes. The cells were identified in peribiliary glands found in the extrahepatic biliary tree, ramifying ducts located between the liver and pancreas [499]. Analysis of cell surface marker and transcription factor expression in situ, along with the growth and differentiation potential of the cells, suggests that they include a population of more primitive endodermal stem cells than the HpSC identified within the liver.…”

The Pharmacology of Regenerative Medicine

“…The scaffold could be augmented with growth factors and additional extracellular matrix components to help drive proliferation and/or differentiation (Turner et al, 2010). Validation of this approach came from a demonstration that delivery in hyaluronan hydrogels greatly improves retention of HpSC (hepatocyte stem cell) in the liver, promoting more efficient engraftment, proliferation, and vascularization (Turner et al, 2013) (Figs. 5-7).…”

The translational imperative: Making cell therapy simple and effective

“…The resulting HA hydrogels, which supported cell attachment, survival and expansion of hHpSC colonies, induced transition of hHpSC colonies towards stable heterogeneous populations of hepatic progenitors depending on the stiffness of the hydrogel, showing that mechanical properties of the microenvironment can regulate differentiation in endodermal stem cell populations. Importantly, human fetal liver progenitor cells also retained a functional phenotype in three-dimensional (3-D) culture, producing significantly lower alpha-fetoprotein and significantly greater EpCAM (a tight junction marker) and albumin production than in a 2-D culture on plastic [19]. …”

“…The Reid group conducted grafting experiments in immune-competent and immune-compromised mice [19]. With the immune- competent C57/BL6 mice, syngeneic murine hepatic progenitor cells (1,500,000 cells) tagged with luciferase were injected into the liver lobes in either buffer suspension or as a partially gelled slurry in the same HA-based sECM hydrogel.…”