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these stem cell derived beta cells to primary beta cells, but this scalable
strategy is promising for clinical application.
3.2.2. Hepatocytes
Hepatocytes are the primary cells creating the liver. Hepatocyte func-
tions include protein synthesis and storage, cholesterol, bile salt, and
phospholipid synthesis, and detoxification and excretion of wastes or
toxic materials. Exposure to toxic chemicals, alcohol abuse, or viral
hepatitis can potentially cause irreversible damage to hepatocytes.
This can lead to chronic liver failure, and liver transplantation repre-
sents the current clinical treatment to address functional tissue loss.
As with any organ transplant, the demand exceeds the availability of
viable organs. Challenges also arise with tissue compatibility and
rejection. Stem cell based therapies for liver disease offer a potential
alternative to restore functional hepatocytes. Additionally, stem cell
derived hepatocytes could be utilized for drug toxicity testing.
Like beta cells, hepatic differentiation requires definitive endo-
derm specification followed by tissue, in this case hepatic, specifica-
tion. In 2005, Schwartz et al. tested the ability of different cytokines
to induce hepatocyte lineage specification in a serum free environ-
ment.^40 They found FGF4 and hepatocyte growth factor (HGF) sig-
nificantly increase the expression of fetal hepatocyte markers, such as
albumin, AFP, and CK18.^40 It has also been shown that the composi-
tion of extracellular matrix substratum used for differentiation culture
may play a role in supporting hepatocyte specification. Culture on
type 1 collagen during directed differentiation produced hepatocyte-
like cells with albumin secretion closest to adult hepatocytes.40,41
In 2007, Cai et al. published a three-stage protocol for the dif-
ferentiation of hESCs to hepatocyte or hepatocyte-like cells.^42 Their
protocol used Activin A for definitive endoderm induction, recog-
nized as particularly important in hepatic differentiation as extraem-
bryonic endodermal cells express some of the same markers as
hepatocytes.^42 FGF4 and BMP2 were utilized to induce hepatic pro-
genitor specification with 70% efficiency for producing cells with fetal
hepatocyte marker expression.^42 After maturation with HGF,
