liver stem-cell

In vertebrates, the liver is the only internal organ that

can regenerate itself

Only 25% of a liver is needed to regenerate an entire

organ via hepatocyte replication

Viral hepatitis (hepatotropic and opportunistic), bacterial, fungal, parasitic

Autoimmune hepatitis, GVHDa (Graft versus host disease), primary biliary cirrhosis

Mushroom ingestion, idiosyncratic drug reaction, acetaminophen, suicide attempt

Inherited metabolic diseases, fatty liver disease

Obstructive cholestasis, vascular disorders, heat stroke, life style and habits

(alcoholism, fast foods, insufficient physical activity, stress), neoplasms (primary

and secondary)

Non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic Steatohepatitis (NASH)

I. Hematopoietic stem cells (HSCs) CD34 and CD133

positive

II. Mesenchymal stem cells (MSCs) that lack a well-defined

surface antigen expression pattern

Limited in number & Variable in quality

Not able to be expanded in vitro

The ability of hepatocytes to effectively repopulate a diseased liver appears to be

limited to a select group of disorders (such as hereditary tyrosinemia, wilson disease,

or progressive familial intrahepatic cholestasis)

Require immunosuppression (insufficient experience to define the amount and

duration of immunosuppression needed in this setting.)

Lastly, how long these hepatocytes will be viable and the nature of their interaction

with native hepatocytes remain unclear

Several approaches are in development, including hepatocytes derived from cell lines,

xenotransplant of animal-derived hepatocytes, and even in vivo expansion of human

hepatocytes in fumarylacetoacetate hydrolase-deficient animal incubators.

Liver stem/progenitor cells (also known as oval cells in rodents) are thought to

represent tissue specific, bipotential precursors to liver parenchymal cells

Transplant of LSPCs has been accomplished

via intrasplenic injection or infusion into a

peripheral vein or the portal vein.

Severe fibrogenic response that is driven by the

activation of the hepatic progenitor compartment

Require immunosuppression

The true ability of LSPCs to transdifferentiate

into mature hepatocytes are not entirely clear.

Adult LSPCs are available only in limited numbers, and there are ethical constraints

on the use of human fetal LSPCs.

Directed differentiation techniques have also allowed

generation of hepatic progenitor cells from human

embryonic stem cells

I. Hematopoietic stem cells (HSCs) CD34 and CD133 positive

II. Mesenchymal stem cells (MSCs) that lack a well-defined surface antigen

expression pattern

True pluripotent stem cells present in bone marrow are estimated to be less than

0.1% of CD133+ cells.

The migration of these stem cells appears to be mediated by a chemoattractant,

such as stromal cell-derived factor; Subsequently, the secretion of interleukin 8,

matrix metalloproteinase 9, hepatocyte growth factor, and stem cell factors

facilitates homing and engraftment of MSCs in the liver.

Transdifferentiation into hepatocytes

Stimulation of native hepatocyte proliferation

Immunomodulatory effects

Cell plasticity

An antifibrotic effect

Hepatic stellate cells and myofibroblasts may derive from bone marrow stem cells

MSCs can undergo malignant transformation

infusion of collected autologous stem cells

mobilization of bone marrow stem cells by the administration of granulocyte

colony-stimulating factor (GC-SF).

Trials of Mesenchymal Stem Cell Transplant in Patients With Chronic Liver Diseases

Reference Cell therapy Dose, route No. of patients Type of study Results

Amer et al, 2011BM-MSC (bone marrowe

derived hepatocytes)

Single dose,

intrahepatic,

intrasplenic

10 Intrahepatic

10 Intrasplenic

20 Controls

Controlled trialLess ascites/edema,

increased albumin

Zhang et al, 2012 UC-MSCMultiple doses,

peripheral vein

30 Treatment

15 Controls

Randomized

controlled trial

Less ascites, decreased

MELD

Mohamadnejadet al, 2007

BM-MSCSingle dose,

peripheral vein4 Uncontrolled trial

Decreased MELD in 2 of

4 patients

Kharaziha et al, 2009 BM-MSCSingle dose,

portal vein8 Uncontrolled trial Decreased MELD

Peng et al, 2011 BM-MSCSingle dose,

hepatic artery

53 Treatment

105 Controls

Randomized

controlled trial

Decreased T Bil, improved

INR and MELD score

Mohamadnejad

et al, 2013BM-MSC

Single dose,

peripheral vein

15 Treatment

12 Placebo

Randomized

controlled trial

No differences between

the groups

BM-MSC ¼ bone marrowederived mesenchymal stem cells; INR ¼ international normalized ratio; MELD ¼ model of end-stage liver

disease; T Bil ¼ total bilirubin; UC-MSC ¼ umbilical cord-derived mesenchymal stem cell.

Trials of Sorted Hematopoietic Stem Cell Transplant in Patients With Chronic Liver Diseases


Gordan et al, 2006 CD34+

Single dose,

portal vein or

hepatic artery

5 Uncontrolled trialSerum albumin improved,

T Bil improved

Mohamadnejadet al, 2007 CD34+

Single dose,

hepatic artery4 Uncontrolled trial

Serum albumin, INR, T Bil

improved

Pai et al, 2008 CD34+Single dose,


CP score improved, T Bil

decreased

Levicar et al, 2008 CD34+Single dose,

hepatic artery5 Uncontrolled trial Improved T Bil

CP ¼ Child-Pugh; INR ¼ international normalized ratio; T Bil ¼ total bilirubin.

Trials of GC-SF-Mobilized Hematopoietic Stem Cell Transplant in Patients With Chronic Liver

Diseases


Yannaki et al, 2006 GC-SF/PBMNCSingle dose,


CP score improved,

MELD score

improved

Gaia et al, 2006 GC-SFMultiple doses

of GC-SF8 Uncontrolled trial Feasibility, safety study

Yan et al, 2007 GC-SF/HGF Unclear 2 Uncontrolled trial

PBMNCs were

transformed in

hepatocyte-like cells

Khan et al, 2007 GC-SF/CD34+Single dose,


Improved serum albumin,

T Bil,

ALT

Han et al, 2008 GC-SF/PBMNCSingle dose,

hepatic artery

20 GC-SF plus

PBMNC

infusion

20 GC-SF

Randomized

controlled trial

GC-SF plus PBMNC

group had

better liver test results

Garg et al, 2012 GC-SF Multiple doses23 Treatment

24 Placebo

Randomized,

blinded,

controlled trial

Improved MELD score,

better

patient survival

ALT ¼ alanine aminotransferase; CP ¼ Child-Pugh; GC-SF ¼ granulocyte colony-stimulating factor; HGF ¼ hepatocyte growth

factor; MELD ¼ model of end-stage liver disease; PBMNC ¼ peripheral blood mononuclear cells; T Bil ¼ total bilirubin.

Direct differentiation technique

ESCs that have been exposed to activin A and Wnt for 3 days formed DE. Then, FGFs and BMPs were

added to cells for 5 days. Early hepatocytes were exposed to hepatocyte growth factor, dexamethasone

and oncostatin M for 10–15 days for additional maturation. ESC-derived hepatocyt-like cells have been

transplanted in animal models with improvement in hepatic function.

Ethical problems and immunologic rejection are main limiting factors as well as

their potential to be teratogenic

Retroviral transduction of Oct4, Sox2, Klf4, and c-Myc genes

(Nanog, Lin28)

Retroviral transduction of Oct4, Sox2, Klf4, and c-Myc genes

Mouse and human iPSCs are highly similar to their respective embryo-

derived SCs counterparts in morphology, molecular and phenotype aspects.

In human iPSCs the evidence of functional differentiation into specialized

cell lineages of all three embryonic germ layers has been demonstrated.

It has been shown that HLCs could also be generated from human iPSCs.

The differentiated HLCs showed several similarities in morphology, the

expression of a set of proteins, such as a-fetoprotein and albumin, and

functionality such as glycogen synthesis, detoxification and engraftment,

after transplantation into a suitable animal model

IT has been shown that HLCs derived from human ESCs and human iPSc

exhibited broad similarity as well as meaningful differences.

Recently, several liver-specific disease iPSCs, such as familial hypercholesterolemia, glycogen

storage diseases, familial hypercholesterolemia, alpha 1-antitrypsin deficiency and Crigler

Najjar syndrome have been launched.

Teratogenicity and their attitude toward malignancy

Unfortunately, it looks this method has a

hard time to convert adult somatic cells

Transplant of LSPCs from various sources has been accomplished via intrasplenic

injection or infusion into a peripheral vein or the portal vein.

Generally, a regenerative stimulus such as partial hepatectomy or retrorsine injection is

required for optimal engraftment

Severe fibrogenic response that is, in fact, driven by the activation of the hepatic

progenitor compartmen

Require immunosuppression (insufficient experience to define the amount and duration

of immunosuppression needed in this setting.)

The true ability of LSPCs to transdifferentiate into mature hepatocytes and the extent

to which this process might contribute to liver regeneration and repair in various

disease states are not entirely clear.

Directed differentiation techniques have also allowed generation of hepatic progenitor

cells from human embryonic stem cells



Liver stem/progenitor cells (also known as oval cells in rodents) are thought to

represent tissue specific, bipotential precursors to liver parenchymal cells

Transplant of LSPCs has been accomplished via intrasplenic injection or infusion into a

peripheral vein or the portal vein.

Severe fibrogenic response that isdriven by the activation

of the hepatic progenitor compartmen

Require immunosuppression

The true ability of LSPCs to

transdifferentiate into mature

hepatocytes are not entirely clear.



Directed differentiation techniques have also

allowed generation of hepatic progenitor cells

from human embryonic stem cells

Trials of Unsorted Bone Marrow-Derived Mononuclear Cell Transplant in Patients With Chronic

Liver Diseases


Lyran et al, 2007 BM-MNCSingle dose,


Decreased T Bil and INR,

increased

serum albumin

Terai et al, 2006 BM-MNCSingle dose,


Improved serum albumin,

total protein,

CP score

Kim et al, 2010 BM-MNCSingle dose,


Less ascites, improved CP

scores,

increased liver volume

Saito et al, 2011 BM-MNCSingle dose,

peripheral vein

5 Treatment

5 Controls

Randomized

controlled trial

Improved CP scores and

INR, higher

serum albumin and total

protein

Lyra et al, 2010 BM-MNCSingle dose,

hepatic artery

15 Treatment

15 Controls

Randomized

controlled trial

Improved serum albumin

and CP score

Spahr et al, 2013 BM-MNC +GC-SF

Single dose,

hepatic artery

28 Treatment

30 Controls

Randomized

controlled trial

No significant differences

between

study groups

BM-MNC ¼ bone marrowederived mononuclear cells; CP ¼ Child-Pugh; GC-SF ¼ granulocyte colony-stimulating factor; INR ¼

international normalized ratio; T Bil ¼ total bilirubin.