g., highly crosslinked HA hydrogels).22 Mature stellate cells produced both network and fibrillar collagens
(large amounts of type I collagen and lower levels of type III, IV, and V collagens), large amounts of elastin, and both HS-PGs and CS-PGs. The levels of all of these were the highest observed in the activated stellate cells and myofibroblasts obtained from adult livers. A primary biological activity of activated hHpSTCs is matrix synthesis, and this includes the production of diverse collagen types (types I, III, IV, and V) and multiple types of basal adhesion molecules (fibronectin and laminin α1 and laminin γ1 chains).23 Disease states such as fibrosis and cirrhosis are associated with highly activated stellate cells, which contribute to scar tissue formation throughout the liver. Indeed, mice defective in the LIM homeobox 2 gene experience early and inappropriate Ruxolitinib supplier activation of stellate cells and spontaneous cirrhosis.24 CS-PGs, detected by immunohistochemical
assays, were present in feeders derived from human fetal livers or hHpSC colonies. They can form complexes with growth factors and chemokines, albeit more weakly than those found for HS-PGs.18, 25, 26 A recent report identified unique forms of CS-PGs with little or no sulfation present in stem cell niches, including the liver.18 The liver’s stem cell niche is dominated by HAs and by forms of CS-PGs that make a nonsulfated (or minimally sulfated) glycosaminoglycan (GAG) selleck chemical 上海皓元 barrier minimizing the presentation of signals (i.e., those bound
to GAGs) to the stem cells. When the stem cells migrate from the niche, they come into contact with GAGs and proteoglycans with more extensive sulfation and stably bound growth factors that are known to influence the stem cells either with respect to growth or with respect to differentiation into various mature cell fates.27 The feeders with the most extensive effects on differentiation are those with the highest levels of HS-PGs, which are renowned for operating as high-affinity chemical scaffolds for growth factors. HS-PGs have been purified from rodent livers by Gallagher and associates28 and from human livers by Linhardt and associates27 and characterized extensively. The maturation of liver parenchymal cells is induced by HS-PGs with a higher degree of sulfation, especially O-sulfation (as found in heparin chains), which in both humans and rodents is associated with the most mature parenchymal cells in the liver.29 The extent of differentiation also correlated with the three-dimensionality, the ratio of type I collagen to other collagen types, the ratio of fibronectin to laminin isoforms, the presence of proteoglycans with moderate to high levels of sulfation (e.g., HS-PG isoforms), and the rigidity of the hydrogels.