Concise review: clinical programs of stem cell therapies for liver and pancreas

Abstract

Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs' effects are primarily via modulation of immune mechanisms.

Keywords: Cell transplantation; DETERMINED (Adult) stem cells; Hematopoietic stem cells; Liver; Mesenchymal stem cells; Pancreas; Tissue regeneration; Tissue specific stem cells.

Figure 1. A. Schematic of the biliary tree

The biliary tree connects the liver and the pancreas to the duodenum. The PBGs found throughout the biliary tree are stem cell niches containing stem cells and progenitors and are in especially high numbers at various branching points of the tree (blue stars). Ultimately they connect into the intrahepatic stem cell niches and into the pancreatic duct glands, niches of committed progenitors within the pancreas. Figure modified from one in Turner et al . B. Schematic of the hepato-pancreatic common duct

Figure 1. A. Schematic of the biliary tree

The biliary tree connects the liver and the pancreas to the duodenum. The PBGs found throughout the biliary tree are stem cell niches containing stem cells and progenitors and are in especially high numbers at various branching points of the tree (blue stars). Ultimately they connect into the intrahepatic stem cell niches and into the pancreatic duct glands, niches of committed progenitors within the pancreas. Figure modified from one in Turner et al . B. Schematic of the hepato-pancreatic common duct

Figure 2. Stem/progenitor cell niches

A and B are peribiliary glands in human biliary tree tissue; sections are stained for SOX17 or PDX1. Note the heterogeneity of cells expressing PDX1 or SOX 17 in these PBGs. Figure modified from one in Cardinale et al.. C. Canals of Hering, stem cell niches for hHpSCs in an adult livers. Figure from Zhang et al, . C1. Enlargement of C and with labeling to show hHpSCs in the canals; hHBs tethered to the ends of the canals of Hering; and hHBs connecting to hepatocytes. D. Pancreatic duct glands (PDGs) containing only committed progenitors stained for SOX2 that is expressed in peribiliary glands but not in pancreatic duct glands. Image is from Wang et al .

Figure 3. Radial axis maturational lineage near liver

Evidence for a maturational lineage progressing from PBGs near the fibromuscular layer to mature cells at the bile duct lumens. EpCAM is an intermediate marker and albumin a more mature marker for the cells that are maturing towards a liver fate. This occurs in the portion of the biliary tree closest to the liver. Figure reproduced from one in Cardinale et al..

Figure 4. Schematic of the network of stem/progenitor cell niches

Schematic of the network of stem/progenitor cell niches from those in the biliary tree to ones in liver and pancreas. Figure provides a few of the markers on subpopulations of stem cells and progenitors in the proximal-to-distal axis (see Table S2 for more details).

Figure 5. Cultures of human biliary tree stem Cells (hBTSCs) and hepatic stem cells (hHpSCs) under self-replication conditions

A-D: Colonies of human biliary tree stem Cells (hBTSCs); E-F: Colonies of hepatic stem cells (hHpSCs). The stem cells have been plated onto culture plastic and in serum-free Kubota’s Medium, a medium designed for endodrmal stem cells and progenitors.

Figure 5. Cultures of human biliary tree stem Cells (hBTSCs) and hepatic stem cells (hHpSCs) under self-replication conditions

A-D: Colonies of human biliary tree stem Cells (hBTSCs); E-F: Colonies of hepatic stem cells (hHpSCs). The stem cells have been plated onto culture plastic and in serum-free Kubota’s Medium, a medium designed for endodrmal stem cells and progenitors.