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452 Part V: Therapeutic Principles Chapter 30: Regenerative Medicine: Multipotential Cell Therapy for Tissue Repair 453

function have been attributed to increased angiogenesis, neurogenesis, clinically sufficient numbers, as they lose their viability and function
prosurvival signals, and mitigation of immune responses. 117,118 These when cultured in vitro.
mechanisms are potentially mediated by various soluble factors that Transplanted human ESC/iPSC-derived mature hepatocytes can
act through a paracrine mechanism secreted by transplanted stem cells express liver-specific enzymes such as albumin, antitrypsin, and cyto-
that benefit the local environment. Many of these secreted factors have chrome P450, which can improve liver function. 136,137 Furthermore,
begun to be identified and are well-known mediators of neurogenesis a functional liver organ bud generated from iPSCs was found to be
(bone-derived neurotrophic factor [BDNF]), angiogenesis (vascular engrafted and integrated within the host organism, even including
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endothelial growth factor [VEGF]), and immune regulation (trans- development of blood vessels. When iPSCs are injected into the
forming growth factor-β [TGF-β ]). 117,119 blastocysts of fumarylacetoacetate hydrolase (FAH)-deficient mice,
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The use of pluripotent cell types (ESCs, iPSCs) holds significant iPSC-derived hepatocytes can repopulate the damaged liver efficiently
potential as a therapeutic approach for CNS repair. Clinical application and restore liver function. 139
of ESCs/iPSCs is limited because of the inability to isolate pure differ- The liver and pancreas both harbor a niche of stem cells, collec-
entiated populations of neuronal cell types. 120,121 Despite this limitation, tively known as the hepatic stem/progenitor cells. 140,141 The fetal biliary
considerable progress has been made in preclinical studies for remy- tree, arising from the ductal plate cells during development and con-
elination following spinal cord injury. 122,123 These studies and others sisting of the intrahepatic and extrahepatic ducts, has been shown to
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have demonstrated that ESCs/iPSCs can be differentiated to oligoden- harbor a rich source of stem/progenitor cells. These stem/progenitor
drocyte progenitor cells (OPCs), migrate within the spinal cord, and cells are quite distinctive from hepatoblasts, which contribute toward
produce myelin. Again, the efficacy and mechanism of recovery remain the hepatocytes or cholangiocytes during development. These stem/
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controversial. 124–127 In 2010, the Geron Company began recruitment of progenitor cells present in the biliary tree differ from hepatoblasts by
patients for a phase I clinical trial for treatment of spinal cord injury their ability to self-renew and differentiate into hepatocytes, cholan-
with ESC-derived OPCs. Despite significant enthusiasm from the giocytes, or pancreatic islets, depending on the microenvironment.
patient population, and report of no adverse events on a small cohort Sox9 expression is detected throughout the pancreatic ducts, intra-
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of treated patients (n = 4), significant methodologic and economic and extrahepatic ducts, and in the intestinal crypt connected through
obstacles forced the early discontinuation of the trial. the major duodenal papilla, forming a contiguous Sox9+ zone. 144,145
Remarkably, when an adenovirus contacting three pancreatic transcrip-
tion factors (Pdx1, Ngn3, and MafA) was delivered into the liver, it was
LIVER AND PANCREAS REPAIR able to reprogram the Sox9+ population of cells within the bile ducts into
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The liver is an essential organ that coordinates glycogen storage, drug functional insulin-secreting, beta-like cells. When both Ad-PNM and a
detoxification, production of various serum proteins, and secretion of peroxisome proliferator-activated receptor (PPAR) agonist, WY14643,
bile, which plays a critical role in food digestion and metabolism. It is were given in animals, it resulted in injury to the liver, led to an increase
interspersed with small microscopic canals known as canaliculi through in the cell division rate of Sox9+ cells lining bile ducts, and contrib-
which the bile drains to the gall bladder. The numerous bile canaliculi uted toward making more insulin-positive beta cells. In an injured
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join together into many larger bile ducts, which join to become a liver, the Wnt signaling pathway is activated, which stimulates discreet
branched structure that forms the common hepatic duct. The part of subsets of progenitor cell populations, which, in turn, engage in liver
the common hepatic duct that is outside the liver is called the extra regeneration. Isolation of stem/progenitor cell populations based on
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hepatic bile duct, which joins the cystic duct from the gall bladder to their surface markers like Lgr5 or EpCAM has identified the possibility
form the common bile duct and connect to the exocrine pancreas. This of differentiating them toward a hepatocyte- or beta-like cell fate. 145,148
whole branched structure forms the biliary tree. Liver, biliary tree, The pancreas plays an important role in digestion, as well as in
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and pancreas originate from the anterior definitive endoderm and have maintaining blood glucose homeostasis. It is composed of ducts, with
been found to share stem cell populations during the early stages of the main duct (pancreatic duct) running the length of the pancreas. The
development. 130 pancreatic duct merges with the bile duct to form the major duodenal
The normal liver has extraordinary potential to regenerate fol- ampulla, which drains the pancreatic fluid into the first portion of the
lowing partial removal of the liver or liver injury. The hepatocytes and small intestine, the duodenum. The pancreas is composed of exocrine
cholangiocytes (biliary epithelial cells) are normally quiescent, but in and endocrine parts. The exocrine component plays an integral part in
response to liver injury, these cells proliferate and contribute to regen- digestion. The endocrine component contains the islets of Langerhans
eration. Average liver turnover is maintained by differentiation and that produce and secrete hormones into the bloodstream. The pancre-
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proliferation of parenchymal or nonparenchymal cells. However, in atic hormones, insulin and glucagon, work together to maintain proper
chronic liver disease, when the liver cannot be repaired by self- sugar levels in the blood.
duplication of existing hepatocytes, small bipotential progenitor cells Diabetes mellitus is a metabolic syndrome caused by having an
are activated that have the ability to differentiate into either hepatocytes insufficient number of insulin-producing beta cells. In type 1 diabetes,
or cholangiocytes. Severe injury in alcoholic liver disease has been beta cells are destroyed by the body’s own immune system. In type 2
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found to stimulate increased proliferation of hepatic stem/progenitor diabetes, although the pancreas has functioning beta cells, insulin resis-
cells in humans and oval cells in rodents. Some experiments have tance causes the liver to release too much sugar into the bloodstream,
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suggested that stem progenitor cells are not only activated in the injured and the beta cells cannot secrete enough insulin to maintain normal
liver, but that the normal adult human liver contains a large number of glucose homeostasis. The American Diabetes Association estimated in
liver progenitor cells that may contribute to liver homeostasis. 2012 that approximately 9.3 percent of the United States population is
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Liver transplantation is currently the only option in acute liver fail- living with diabetes. Beta-cell therapy holds promise for treating
ure. Two small clinical trials conducted with hepatocyte transplantation type 1 diabetes by replenishing beta cells in the body; however, donor
resulted in limited restored enzyme function in one patient, but it was pancreases are in short supply and the demand for transplantable beta
not enough for survival and the patient eventually needed a liver trans- cells cannot be met.
plant. It remains unknown if hepatocytes can contribute to long-term In addition, beta-like cells have been successfully generated
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rescue in patients. Additionally, hepatocytes are difficult to produce in from hESCs and iPSCs using overexpression of transcription factors,

Kaushansky_chapter 30_p0447-0458.indd 452 9/17/15 6:07 PM