Stem Cell Therapy vs.

Liver Transplant
By

Stem cells have the capability of forming different types of cells in our body. In this project, their role in treatment Liver Cirrhosis as a replacement of organ transplant is emphasized.

Acknowledgements
I am highly indebted Mrs. for her guidance and constant supervision as well as for providing necessary information regarding the project & also for her support in completing the project. I would also like to thank my parents for their support.

Stem Cell Therapy vs. Liver Transplant

Page 2

Certificate of Appreciation
I,*** , certify that the project is authentic in its entirety and was completed under my constant supervision by **

Mrs. ***

Stem Cell Therapy vs. Liver Transplant

Page 3

Index Serial No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Title Liver Cirrhosis- Questions We come across What Is Liver Cirrhosis? Causes Symptoms Is transplant the only option? Success of Live transplant Mechanism Search For Donors Limitations Stem Cells: Definition Importance Types Source Liver Regeneration Cell Based Strategies Different Types of cells used in Stem Cell therapy Stem Cell Therapy Overview Stem Cell Research Data Case Study-9 year old requiring immediate transplant. Summery & Conclusion Bibliography
Stem Cell Therapy vs. Liver Transplant

Page No. 5 7 8 9 11 14 16 19 21 22 23 24 25 27 29 31,33,35-37 37 38 39-41 42-44 45 46-47

Page 4

Questions we come across.

Stem Cell Therapy vs. Liver Transplant

Page 5

Normal Liver

Cirrhotic Liver

Stem Cell Therapy vs. Liver Transplant

Page 6

What is Liver Cirrhosis?

Cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injury. Scar tissue replaces healthy liver tissue, partially blocking the flow of blood through the liver.

How does it affect the individual

Cirrhosis affect's the liver's ability to: control infections remove bacteria and toxins from the blood process nutrients, hormones, and drugs make proteins that regulate blood clotting produce bile to help absorb fatsincluding cholesteroland fat-soluble vitamins

Also Increases the pressure in portal venous system.

Stem Cell Therapy vs. Liver Transplant
Page 7

Causes of liver cirrhosis

Hepatitis C Virus Long term Alcohol abuse

Autoimmune inflammation of liver

Hepatitis B Virus

Metabolic Diseases of
Copper -Wilson's Disease Iron-Hemochromatosis

Nonalcoholic fatty liver disease(NAFLD)

Nonalcoholic Steatohepatitis(NASH)

Reaction to certain Medicines.

Stem Cell Therapy vs. Liver Transplant

Page 8

Symptoms
Symptoms may develop gradually, or there may be no symptoms. When symptoms do occur, they can include:
Abdominal indigestion or pain Confusion or problems thinking Impotence, loss of interest in sex, and breast development (gynecomastia) in men Nausea and vomiting Ascites(Ascites is excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity). Nosebleeds or bleeding gums Pale or clay-colored stools Small, red spider-like blood vessels on the skin Vomiting blood or blood in stools

Stem Cell Therapy vs. Liver Transplant

Page 9

Stem Cell Therapy vs. Liver Transplant

Page 10

Ascites

Is liver transplant the only option?

In early stages, no. Following changes in life style may slow down the progression of the disease. Stop drinking alcohol. Get vaccinated for hepatitis A and hepatitis B, and pneumococcal pneumonia Tell your doctor about all prescription and nonprescription medications, and any herbs and supplements you take now or are thinking of taking. Other treatment options are available for the complications of cirrhosis: Bleeding varices -- upper endoscopy with banding and sclerosis Excess abdominal fluid (ascites) -- take diuretics, restrict fluid and salt, and remove fluid (paracentesis) Confusion or encephalopathy -- lactulose medication and antibiotics But in end stages,yes, Liver transplant is the only viable option.

Stem Cell Therapy vs. Liver Transplant

Page 11

Stem Cell Therapy vs. Liver Transplant

Page 12

The liver is the second most commonly transplanted major organ, after the kidney, so it is clear that liver disease is a common and serious problem in this country. It is important for liver transplant candidates and their families to understand the basic process involved with liver transplants, to appreciate some of the challenges and complications that face liver transplant recipients (people who receive livers), and to recognize symptoms that should alert recipients to seek medical help.

Stem Cell Therapy vs. Liver Transplant

Page 13

Success of liver transplant procedures

Liver transplantation has in the past few years evolved from a semi-experimental procedure practiced in only a few European and North American centers to an almost routine worldwide treatment for a whole range of liver diseases.The number of cases saw a huge jump especially in India and other south asian countries. Concurrently, one year survival has improved from less than 50% to more than 90% for certain diagnoses such as biliary atresia, most survivors being able to resume a normal lifestyle. The rate of liver graft loss beyond one year is much lower than for renal and other grafts. Although the surgery and immediate postoperative care are confined to specialist units, further follow up is often undertaken in the patient's local hospital and so more and more clinicians and pathologists are coming into contact with this group of patients. The large majority of liver transplants use the entire liver from a non-living donor for the transplant, particularly for adult recipients.
Stem Cell Therapy vs. Liver Transplant
Page 14

Stem Cell Therapy vs. Liver Transplant

Page 15

Basic mechanism of liver transplantaion

Virtually all liver transplants are done in an orthotopic fashion, that is, the native liver is removed and the new liver is placed in the same anatomic location. The transplant operation can be conceptualized as consisting of the hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the postimplantation phase. The operation is done through a large incision in the upper abdomen. The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, hepatic vein and portal vein. The donor's blood in the liver will be replaced by an ice-cold organ storage solution, such as UW (Viaspan) or HTK until the allograft liver is implanted. Implantation involves anastomoses (connections) of the inferior vena cava, portal vein, and hepatic artery. After blood flow is restored to the new liver, the biliary (bile duct) anastomosis (link) is constructed, either to the recipient's own bile duct or to the small intestine.

Stem Cell Therapy vs. Liver Transplant

Page 16

Stem Cell Therapy vs. Liver Transplant

Page 17

Hepatocytes- Normal Liver Cells

Liver Cirrhosis at 40x Magnification

Stem Cell Therapy vs. Liver Transplant

Page 18

The search for a donor

Once a person is accepted for transplantation, the search for a suitable donor begins. All people waiting are placed on a central list at UNOS. Local and national agencies are involved in finding suitable livers. The United States has been divided into regions to try to fairly distribute this scarce resource. Many donors are victims of some sort of trauma and have been d eclared brain dead. A donor with the right blood type and similar body weight is sought to help reduce the risk of rejection. Rejection occurs when the patient's body attacks the new liver. With the shortage of donor organs and the need to match donor and patient blood and body type, the waiting time may be long. A patient with a very common blood type has less chance of quickly finding a suitable liver because so many others with his or her blood type also need livers. Thus we see that transplantation is not the best possible treatment for Liver Cirrhosis.

Stem Cell Therapy vs. Liver Transplant

Page 19

Diagrammatic representation of liver transplantation.

Stem Cell Therapy vs. Liver Transplant

Page 20

Limitations Of Liver Transplantation.

Lifelong Immunosuppression Cost Availability Shortage of donors High mortality during waiting period
Stem Cell Therapy vs. Liver Transplant
Page 21

Definition
Stem cells are biological cells found in all multicellular organisms, that can divide (through mitosis) and differentiate into diverse specialized cell types and can self-renew to produce more stem cells.

Stem Cell Therapy vs. Liver Transplant

Page 22

Importance
They are capable of forming most of the cells in our body and thus can be used in replacement of dead/ nonfunctional cells and can miracuosly save individuals who might be paralysed for life.

Stem Cell Therapy vs. Liver Transplant

Page 23

Types of Stem Cells

Totipotent

Can construct a complete, viable organism Eg.cells of first few divisions of fertillised egg.

Can form most of the cells. Eg. cells obtained from the three germ layers. Pluripotent

Can diffrentiate into a number of cells but belong to a similar family of cells. Multipotent Eg. cells obtained from liver, Bone Marrow.

Stem Cell Therapy vs. Liver Transplant

Page 24

Placenta
Umbilical cord

Blood

Liver

Sources of Stem Cells

Adipose Tissue

Foetus

Bone Marrow

Stem Cell Therapy vs. Liver Transplant

Page 25

Placenta and EmbryoSources of Totipotent Stem Cells

Stem Cell Therapy vs. Liver Transplant

Page 26

Liver Regeneration
One of the defining features of the liver is the capacity to maintain a constant size despite injury. Although the precise molecular signals involved in the maintenance of liver size are not completely known, it is clear that the liver delicately balances regeneration with overgrowth. Mammals, for example, can survive surgical removal of up to 75% of the total liver mass. Within 1 week after liver resection, the total number of liver cells is restored. Moreover, liver overgrowth can be induced by a variety of signals, including hepatocyte growth factor or peroxisome proliferators; the liver quickly returns to its normal size when the proliferative signal is removed. One of the primary reasons for this controversy is the use of multiple definitions for the hepatic stem cell. Definitions for the liver stem cell include the following: (1) cells responsible for normal tissue turnover (2) cells that give rise to regeneration after partial hepatectomy, (3) cells responsible for progenitor-dependent regeneration, (4) cells that produce hepatocyte and bile duct epithelial phenotypes in vitro, and (5) transplantable liver-repopulating cells.

Stem Cell Therapy vs. Liver Transplant

Page 27

Stem Cell Therapy vs. Liver Transplant

Page 28

Cell based strategies are of two types : 1. Direct infusion of adult /fetal hepatocytes. 2. Infusion of stem cells. 1. Hepatocyte transplant as an alternative a. It has been in use for more than 30 years. However the problem with hepatocyte transplantation is that of availability of adult/fetal human hepatocytes in adequate numbers. The other problem is that they still require immunesuppression.). Xenogenic hepatocyte transplantation has also been tried however it has got lurking fear of retroviral transmission and tumor genesis. 2. Stem cell therapy as an alternative of liver transplantation a. Cellular based therapies promise a great future for a variety of diseases involving various organs. It has been used in conditions as diverse as degenerative disorders of musculoskeletal system and CNS, cardiomyopathy and trauma. In liver diseases the stem cells have been utilized in various metabolic genetic diseases with presentation of proof of principle.
Stem Cell Therapy vs. Liver Transplant
Page 29

Cells Responsible for Normal Liver Tissue Turnover

Hepatocyte replacement occurs relatively slowly; the average life span of adult hepatocytes ranges from 200 to 300 days. A number of different hypotheses have been proposed to explain hepatocyte turnover. In one of the earliest models, called streaming liver, normal liver turnover was proposed to be similar to intestinal regeneration, with young hepatocytes originating in the portal zone and then migrating toward the central vein.

Cells That Give Rise to Regeneration After Partial Hepatectomy

Cells That Give Rise to Regeneration After Partial Hepatectomy Partial hepatectomy is a surgical procedure in which specific liver lobes are removed intact without damage to the lobes left behind. The process has been extensively studied and is the subject of several excellent reviews. The excised liver lobes never grow back, but the remaining lobes grow to compensate for the mass of the resected tissue. Reconstitution of the entire liver mass, which is complete within 57 days in rodents, is mediated by mature cell types (ie, without stem cells).
Stem Cell Therapy vs. Liver Transplant
Page 30

Stem Cell Therapy vs. Liver Transplant

Page 31

Multipotent adult progenitor cells as hepatocyte progenitors

Multipotent adult progenitor cells are a unique population of progenitors from multiple mammalian species that are generated in longterm culture by plating nonhematopoietic adherent cells from the bone marrow.These cells have been reported to have properties similar to embryonic stem cells in that they can be differentiated toward multiple lineages in vitro under the appropriate conditions. When grown on Matrigel with fibroblast growth factor 4 and hepatocyte growth factor, multipotent adult progenitor cells generate hepatocyte-like cells that synthesize urea, secrete albumin, and induce cytochrome p450 in response to phenobarbital.

Amniotic stem cells.

Human amniotic fluid and membranes have been used as sources of pluripotent cells, which are capable of differentiating into endoderm. Specific protocols for the induction of the hepatic phenotype have been developed and are similar to the differentiation regimens used for other progenitors.79 The hepatocyte- like cells that have been generated using the most optimized regimens express cytochrome p450 and other genes that Stemtypical of hepatocytes are Cell Therapy vs. Liver Transplant
Page 32

Stem Cell Therapy vs. Liver Transplant

Page 33

Hepatocytes as LiverRepopulating Cells

Liver repopulation is unique among organ systems. In contrast to the hematopoietic system, where mature adult blood cells have minimal proliferative capacity, differentiated hepatocytes themselves have high capacity for liver repopulation. First, mature hepatocytes (identified by size fractionation, retroviral marking, or serial transplantation) were transplanted into livers of Fah knockout mice. Large, binucleated hepatocytes that represented 70% of the hepatocyte population were found to mediate most of the liver repopulation.

Stem Cell Therapy vs. Liver Transplant

Page 34

Types Of Stem Cells employed in Liver transplantation

Basically three types Embryonic Fetal Adult Embryonic: Omnipotent Can differentiate into any cell type Limitations of availability, ethical issues Fetal: Totipotent Source is 20-24 week fetus Limited supply ADULT HEPATOCYTES

Mature hepatocytes : Problems

Maintaining the stability of metabolic function Difficulties in cryopreservation Immunogenicity Cannot proliferate in vitro

Stem Cell Therapy vs. Liver Transplant

Page 35

Stem Cell therapy

Transplantable Liver-Repopulating Cells One of the hallmarks of tissue-specific stem cells is their capacity to repopulate a specific organ and restore its function. HSCs, for example, were identified based on their ability to reconstitute blood lineages in lethally irradiated hosts. Over the past 2 decades, similar assays were developed to identify liver stem cells; a small number of transplanted donor cells were found to engraft in the liver and expand to replace 50% of the liver mass. Such models allow for the replacement of only hepatocytes by transplanted cells. Efficient repopulation of the biliary system has not been reported, but it is possible to functionally evaluate hepatic stem cell populations based on their capacity for liver repopulation.

Stem Cell Therapy vs. Liver Transplant

Page 36

Overview:
Problems with Liver Transplantation: High cost.(20 lakhs in India) Prolonged and complicated surgery. High mortality , high morbidity and variable success rate. Post transplant immunosupression is a problem Rejction can occur. Lack of available of cadaveric livers and/or live related donors. Donor morbidity/ mortality. Stem Cells overcomes most of the limitations: Relativity low cost (1.25 lakh) No surgical complications involved Age is not a barrier 100% success rate Cases where the patient has died and very rare

Stem Cell Therapy vs. Liver Transplant

Page 37

Stem Cell Therapy vs. Liver Transplant

Page 38

Stem Cell Therapy vs. Liver Transplant

Page 39

Stem Cell Therapy vs. Liver Transplant

Page 40

Case Study

Stem Cell Therapy vs. Liver Transplant

Page 41

Stem Cell Therapy vs. Liver Transplant

Page 42

Stem Cell Therapy vs. Liver Transplant

Page 43

Stem Cell Therapy vs. Liver Transplant

Page 44

Summary & Conclusion:

The ability of stem cells to form new hepatocytes has proved to be a boon for patients all over the world suffering from a number of liver related diseases such as Liver Cirrhosis. In the past, liver transplantation was the only option, but with the help of latest technology and our knowledge of stem cells, we can now use Stem Cell Therapy as a new methodology of curing liver diseases. In the overview section, we saw how they are beneficial over transplantation and thus we can conclude that stem cells have a bright future not just in hepatology but in a wide variety of fields.

Stem Cell Therapy vs. Liver Transplant

Page 45

Bibliography:
Stem Cells and Liver Regeneration- Andrew W. Duncan, Craig Dorrell, Markus Grompe. The copyright is free of charge. http://www.gastrojournal.org/article/S00165085%2809%2900818-X/abstract

Www.Wikipedia.com some basic definitons http://www.microscopyu.com/galleries/pathology/index .html image of cirrhotic liver cell.
Stem Cell Therapy vs. Liver Transplant
Page 46

 http://www.vivo.colostate.edu/hbooks/pathphys/digesti on/liver/histo_glycopas.jpg image of normal liver cell http://liver-transplantation.blogspot.com/ diagram of liver transplantation. Special thanks to Dr. *** for data and Case Studies.

Stem Cell Therapy vs. Liver Transplant

Page 47