Corresponding Author: Deby Susanti Pada Vinski
E-mail: [email protected]
INTRODUCTION
Chronic liver
diseases, including cirrhosis, hepatitis, and nonalcoholic fatty liver disease,
represent a significant global health burden, affecting millions of people
worldwide (Asrani et al., 2019). Despite advances in medical treatment, liver transplantation
remains the definitive therapy for end-stage liver disease. However, organ
shortage, surgical complications, and the need for lifelong immunosuppression
limit transplantation's widespread availability and efficacy (Khalil et al., 2023).
In recent
years, regenerative medicine approaches utilizing stem cells have emerged as
promising therapeutic strategies for liver regeneration and functional
recovery. Among these, mesenchymal stem cells (MSCs) derived from various
sources, including bone marrow, adipose tissue, and umbilical cord blood, have
garnered considerable attention due to their multipotent differentiation
capacity, immunomodulatory properties, and paracrine effects (Han et al., 2019); (Nazarian et al., 2021).
����������� This
study investigates the potential of MSCs derived from umbilical cord blood to
promote liver function recovery in preclinical and clinical settings.
Specifically, it aims to evaluate the therapeutic efficacy, safety profile, and
mechanisms of action underlying MSC-based therapies in liver regeneration and
repair.
This research
contributes to the growing body of knowledge on stem cell-based therapies for
liver diseases by providing insights into the regenerative potential of MSCs
derived from umbilical cord blood. By elucidating the mechanisms by which MSCs
promote liver regeneration, the study seeks to inform the development of novel
therapeutic interventions to improve clinical outcomes for patients with liver
disease.
Furthermore,
this research has translational implications for developing MSC-based
regenerative therapies that could reduce the need for liver transplantation and
offer alternative treatment options for patients with advanced liver disease.
Additionally, by exploring the safety and feasibility of MSC transplantation in
clinical trials, this study aims to pave the way for the broader adoption of
stem cell-based therapies in managing liver diseases, addressing unmet medical
needs and improving patient quality of life.
Research into
stem cell therapy for liver disease is a rapidly evolving field with
significant potential. However, there are several gaps and challenges that need
to be addressed to advance this therapy effectively. Mechanisms of Action like how to understanding Mechanisms : More research
is needed to fully understand the mechanisms through which stem cells
contribute to liver regeneration. This includes their interaction with the
liver microenvironment, immune modulation, and differentiation into hepatocytes.
Long-Term Effects �Long-term effects and
integration of stem cells in the liver tissue are not well understood. Addressing
these gaps through coordinated research efforts, interdisciplinary
collaboration, and robust clinical trials will be essential to realize the full
potential of stem cell therapy for liver disease recovery.
However,
there are several gaps and challenges that need to be overcome for this therapy
to work effectively starting from the Mechanism of Action such as how to
understand the Mechanism. More research is needed to fully understand the
mechanisms through which stem cells contribute to liver regeneration. The
long-term effects and integration of stem cells in liver tissue are not well
understood. Addressing these gaps through coordinated research efforts,
interdisciplinary collaboration, and robust clinical trials will be critical to
realizing the full potential of stem cell therapy for liver disease recovery.This
study reviews the potential of mesenchymal stem cells (MSCs) for liver
regeneration, highlighting their immunomodulatory properties and ability to
differentiate into hepatocyte-like cells.
Causes of Liver Disease
Viral Infections
����������� Hepatitis
A is an RNA virus belonging to the Picornaviridae family. It is present in the
highest concentration in the stool of infected persons, where the most
significant release of the viral load is at the end of the incubation period.
Hepatitis A is most often transmitted through the faecal-oral route from contact
with water, food, or objects contaminated with the faeces of an infected person
(Koenig et al., 2017). Primarily, the hepatitis A virus replicates in hepatocytes. At
the same time, animal studies suggest possible replication in epithelial cells
of tubular crypts and lamina propria cells. After ingestion, the virus from the
gastrointestinal tract will take over, and its particles are transported to the
basolateral membrane of hepatocytes via the portal circulation. In acute
hepatitis A infection, hepatocellular injury is mediated by various
immunological mechanisms. Patients with acute infection with hepatitis A virus
have a specific release of cytotoxic interferon-gamma that is virus-specific
and mediated by T cells. After replicating in the, the hepatitis A virus is
secreted through the gums and released in the stool (Iorio & John, 2023).
����������� Hepatitis
B virus is a DNA virus that belongs to the Hepadnaviridae family. The viral
core consists of the nucleocapsid, hepatitis B core antigen (HBcAg), which
surrounds the viral DNA and DNA polymerase (Mehta & Reddivari, 2021). The hepatitis B surface antigen (HBsAg) is coated on the
nucleocapsid. HBsAg is a surface polypeptide. The gene that codes for HBcAg
also codes for hepatitis B e antigen (HBeAg). Hepatitis B virus has eight
genotype variants (You et al., 2014). Hepatitis B virus is transmitted by mucosal exposure to
infectious body fluids or percutaneous inoculation. Although very rare,
oral-fecal transmission is possible. The incubation period of the hepatitis B
virus is between 30 and 180 days. HBsAg is transmitted through contact with
body fluids or blood. At the same time, the risk of infection is higher in
people in close contact with HBsAg positive. The pathogenesis of liver disease
in hepatitis B virus infection is immunologically mediated. Sometimes, the
infection can cause direct cytotoxic liver injury (Chisari et al., 2010).
����������� HBsAg
and other nucleocapsid proteins on cell membranes promote T cell-induced lysis
of hepatitis B virus-infected cells. The cytotoxic response of T cells to
hepatitis B virus-infected hepatocytes is relatively ineffective. In contrast,
most hepatitis B virus DNA is cleared from the liver system before maximal
infiltration of T cells. This indicates that the immune response is more robust
in the early phases of the virus infection. However, the immune response is
potentially not the only aetiology of liver injury in patients infected with
the hepatitis B virus. Injuries associated with hepatitis B virus have also
been observed in patients with hepatitis B virus after liver transplantation
who adhere to immunosuppressive therapy. The histological pattern of infection
in patients after liver transplantation is called fibrosing cholestatic
hepatitis and is thought to be associated with high HBsAg expression,
suggesting that the hepatitis B virus may be pathogenic regardless of the
immune response (Chisari et al., 2010).
Hepatitis C
is an RNA virus belonging to the Flaviviridae family with one serotype, at
least six major genotypes, and more than 80 subtypes (Mehta & Reddivari, 2021). It is most often transmitted through the sharing of infected
needles among people who use IV drugs. It can also be transmitted parentally,
perinatally, and sexually. Other people at high risk of hepatitis C are people
who frequently need blood transfusions or organ transplants from an infected
donor (Li & Lo, 2015).
Hepatitis C
virus enters hepatocytes through endocytosis, which is mediated by at least
four receptor molecules. After internalization in the cytoplasm, the
positive-stranded RNA is unlabeled and translated into ten mature peptides.
Peptides are then cleaved with the help of host proteases and virally encoded
proteases (NS3-4a serine proteases). Mature peptides reside on the endoplasmic
reticulum, where a replication complex is formed that contains the enzyme NS5B
RNA-dependent RNA polymerase, which catalyzes the positive RNA chain into its
negative chain intermediate, which serves as a template for the synthesis of a
new RNA positive chain. Next, the new positive RNA is packaged with the core
and enveloped glycoprotein into mature virions that exit the cell via
exocytosis. The hepatitis C virus can integrate into the host's genome.
Persistent hepatitis C virus infection is thought to occur due to weak CD8+ and
CD4+ T cell responses, which cannot control viral replication. After the
establishment of chronic hepatitis C virus infection, it is no longer a
cytopathic but a local inflammatory response that triggers fibrogenesis.
Accelerated progression of fibrosis and cirrhosis are associated with various
external factors, including coinfection with HIV or hepatitis B, alcohol
consumption, obesity, insulin resistance, nonalcoholic fatty liver disease,
etc.
The Hepatitis
D virus is an RNA virus belonging to the genus Deltavirus (Mehta & Reddivari, 2021). It consists of the hepatitis D antigen (HDAg), RNA genome, and
lipoprotein envelope of the hepatitis B virus. The hepatitis D virus genome
encodes only HDAg. Replication takes place in hepatocytes. The Hepatitis D
virus is unique because it uses the host's RNA polymerase II to transcribe its
messenger RNA (mRNA). There are two HDAgs, i.e. long and short. Short HDAg
activates viral replication through direct binding to hepatitis D virus RNA.
In contrast,
long HDAg directs viral assembly and inhibits viral replication. The virus is
fully assembled after incorporating the herpesvirus B envelope, after which the
virus is released (Ni et al., 2014). Hepatitis D virus infection occurs only when hepatitis B virus
is present. Coinfection of hepatitis B and D in persons susceptible to
hepatitis B virus infection leads to acute infection. Coinfection clinically
resembles acute hepatitis B, except that a biphasic course of two levels of
serum alanine aminotransferase (ALT) can be observed a few weeks apart. This
happens because hepatitis B infection must first be established during acute
coinfection before the spread of the hepatitis D virus begins (Masood & John, 2017).
Hepatitis E
is an RNA virus that belongs to the genus Hepevirus. The fecal-oral route is
the primary way of transmission, and it can also be transmitted through fecally
contaminated water. Person-to-person transmission is rare, while
mother-to-newborn transmission has occasionally been reported (P�rez-Gracia et al., 2015). The Hepatitis E virus targets hepatocytes, and it is thought
that the virus replicates enterally because ORF2 antigens and RNA of the
hepatitis E virus have been found in the intestinal crypts of chronically
infected patients. It is believed that the hepatitis E virus enters the portal
circulation and infects hepatocytes, leading to inflammation. However, the
mechanism of hepatitis E virus entry into hepatocytes is not fully understood (Iqbal et al., 2023). After the virus enters the hepatocyte, the hepatitis E virus
genome is released in the cytoplasm, and the virus hijacks the intracellular
machinery for the replication of vital proteins and the RNA genome. ORF4 is
essential for replication, while ORF3 is necessary for virus release from
infected cells. The combination of human immune response and cellular immunity
limits viral replication, allowing the host to clear the infection.
Anti-hepatitis E virus immunoglobulin M (IgM) antibodies in acutely infected
patients reach their maximum at six weeks, followed by anti-hepatitis E virus
IgG antibodies for long-term protection lasting years to decades. Acute
hepatitis E virus infection is associated with elevated T cells, increased CD8+
and CD4+ cells, and additional release of the anti-inflammatory and
pro-inflammatory cytokines interferon-gamma (IFN-gamma) and interleukin 10
(IL-10). Further immunological protection is provided by the innate response of
lymphoid cells with natural killer cells that fight cell-mediated cytotoxicity
IFN-gamma production and viral infection. The immune response that is
responsible for organizing hepatitis E virus infection is also the cause of
hepatocellular damage and liver inflammation (Iqbal et al., 2023).
The Hepatitis
G virus is an RNA virus belonging to the Flaviviridae family. Primarily, the
virus is transmitted through infected blood and blood products. Hepatitis G
virus infection usually occurs as a coinfection with chronic hepatitis C or
hepatitis B. Although the hepatitis G virus is associated with chronic liver
disease, it has not been established that it causes hepatitis by itself (Soleiman-Meigooni et al., 2015). In addition to hepatitis virus, other viruses such as
Varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, and
cytomegalovirus (Mehta & Reddivari, 2021) can cause hepatitis or liver diseases such as Dengue virus,
Hantavirus, yellow fever virus, Lassa virus, Junin virus, Chikungunya virus,
Congo-Crimea Hemorrhagic fever virus, Rift Valley fever virus, Marburg virus,
Adenoviruses and Ebola virus (Spengler, 2020).
An Autoimmune Disease That Causes
the Body's Immune System to Attack Healthy Cells or Tissue in the Liver �
Autoimmune Hepatitis
Autoimmune
hepatitis is a condition in which cells of the immune system attack and destroy
liver cells. The etiology of autoimmune hepatitis is still unknown.
Pathogenesis is thought to be secondary to the failure of immunological
tolerance in genetically susceptible individuals, which leads to
T-cell-mediated inflammation caused by various environmental triggers. Toxins,
drugs, or infections usually trigger autoimmune hepatitis. Specific human
leukocyte antigen (HLA) haplotypes are more susceptible to developing
autoimmune hepatitis. In different ethnic groups, there are different
susceptible alleles. In Northern Europeans and North Americans, susceptible
alleles are located on the short arm of chromosome 6, that is, the DRB-1
region. Autoimmune hepatitis has been associated with tumour necrosis
factor-alpha. At the same time, minocycline and nitrofurantoin (Linzay et al., 2021), methyldopa, infliximab, adalimumab, and minocycline have been
documented as drugs causing autoimmune hepatitis (Linzay et al., 2021); (Mehta & Reddivari, 2021). However, after stopping treatment with drugs that cause
autoimmune hepatitis, the disease improves (Mehta & Reddivari, 2021).
Genetic Factors
Liver
diseases caused by gene mutations are defined as monogenic liver diseases or
hereditary liver diseases. They mostly have overlapping phenotypes and lack
specific laboratory test indicators (Fang et al., 2021). Genetic causes lead to a wide range of liver function disorders,
including alpha-1 antitrypsin deficiency, Wilson's disease, Gilbert's syndrome,
hemochromatosis, Lysosomal acid lipase deficiency (LAL-D), progressive familial
intrahepatic cholestasis (PFIC), and benign recurrent intrahepatic cholestasis
(BRIC). The C252Y mutation in the HFE gene is the most common cause of
hereditary chromatosis. Alpha-1 antitrypsin deficiency is an autosomal
recessive disease that can cause liver disease (elevated bilirubin and
transaminases, or/and liver cirrhosis) and panacinar emphysema. Wilson's
disease is caused by possessing an autosomal recessive mutation of the ATP7B
gene, which leads to the accumulation of copper in the liver, brain, cornea,
and kidneys, which can manifest as various diseases. PFIC occurs due to PFIC3,
PFIC2, and PFIC1 mutation, leading to chronic cholestasis. BRIC also occurs due
to a PFIC gene mutation, with the disease occurring as episodes of cholestasis (Schonfeld & Brown, 2019). New sequencing technologies have contributed significantly to
understanding the genetics of liver disease and have already led to new
treatments, diagnostic methods, management, etc. (Konkwo et al., 2024).
The Habit of Consuming Excessive
Alcoholic Drinks
Alcoholic
liver disease includes several liver disorders, including fatty liver that can
progress to alcoholic hepatitis and alcoholic liver cirrhosis, which is the
most irreversible and advanced form of alcohol-related liver damage. The three
histological stages of alcoholic liver disease are steatosis or alcoholic fatty
liver, alcoholic hepatitis, and alcoholic cirrhosis. In the stage of steatosis,
mass accumulates in the liver parenchyma. Then, as the disease progresses to
alcoholic hepatitis, liver cell inflammation occurs, where the outcome depends
on the severity of the damage. Alcoholic hepatitis can be treated with alcohol
abstinence, infection treatment, nutritional support, and prednisolone therapy.
However, in severe cases, alcoholic liver hepatitis leads to liver failure.
Alcoholic cirrhosis represents liver damage that is irreversible and leads to
complications of cirrhosis and portal hypertension (Patel et al., 2021).
Unhealthy Eating Patterns
Diet is one
of the environmental factors that influence the development of nonalcoholic
fatty liver disease (NAFLD). An increased intake of red meat is associated with
a higher risk of NAFLD. In contrast, a reduced risk is associated with the
intake of fruits, cereals, and tea, as well as with the development of
cirrhosis and liver cancer (Guo et al., 2022). Increased poultry meat intake and reduced cheese intake are also
associated with an increased risk of NAFLD (Guo et al., 2022).
Obesity
Obesity is a
known risk factor for liver injury, including NAFLD. It may be caused by
excessive fat accumulation, leading to excessive hepatic fatty acid supply,
liver injury, and chronic low-grade inflammation (Luo & Lin, 2021). The body mass index is used as a group of measures of general
obesity. However, waist circumference is a better index of abdominal obesity
and is strongly associated with abdominal fat distribution. Abdominal obesity
and general obesity have been suggested to be a risk factor for liver injury.
General obesity has a more significant influence on the association with liver
enzyme levels and the prevalence of abnormal liver enzymes than abdominal
obesity (Huang et al., 2023).
Drug Abuse
Drug-induced
hepatotoxicity is a chronic or acute liver injury that occurs as a result of
the consumption of drugs or herbal compounds. More than 1000 drugs and herbal
compounds cause hepatotoxicity. Drug-induced liver injury can be intrusive and
idiosyncratic (Francis & Navarro, 2020). After cannabis, the second and third most commonly abused drugs
are opioids and cocaine. Although opioids are generally not involved in a large
number of cases of acute liver injury, they do lead to liver injury. However,
cocaine affects the liver by causing liver necrosis, while liver enzymes change
only after two days of use. Damage to the liver by cocaine is accompanied by
damage to other organs, such as kidney failure, myocardial infarction, and
rhabdomyolysis. Cocaine leads to necrosis of the liver, where there is a
markedly higher level of aminotransferase and lactate dehydrogenase with a
minimal increase in alkaline phosphatase. After acute liver injury, bilirubin
increases two to three days later than liver enzymes. In some instances,
recovery is self-limited when liver enzymes decrease over two weeks (Dolkar et al., 2022)
Exposure to Toxic Chemical
Compounds
Environmental
and occupational exposure to industrial chemicals can lead to liver damage and
hepatotoxicity in humans and animals (Lang & Beier, 2018). Compounds that have been shown to cause liver injury include
leachable organic substances (Lang & Beier, 2018), perfluorinated alkyl substances (Sen et al., 2022), organic solutions (dimethylformamide, dimethylacetamide,
trichloroethylene, tetrachloroethylene, carbon tetrachloride, xylene, toluene,
and chloroform; (Malaguarnera et al., 2012), vinyl chloride, toxic oil syndrome, aflatoxins, anilines (Wahlang et al., 2013), chemical compounds in cigarette smoke (Barouki et al., 2023), etc.
Cancer Cell Growth
Hepatocellular liver cancer is the primary
cancer with the highest prevalence of liver cancer. So far, several
histological subtypes of hepatocellular carcinoma of the liver are known,
including CAP carcinoma, transitional liver cell tumour, steatohepatitic
hepatocellular carcinoma, diffuse cirrhosis-like hepatocellular carcinoma,
clear cell hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma,
combined hepatocellular carcinoma, cholangiocarcinoma, fibrolamellar carcinoma,
and scirrhous hepatocellular carcinoma (Bisteau et al., 2014).
In recent years, gene sequencing has described
the association of several genes with hepatocellular carcinoma. However, most
of the genetic events that promote hepatocellular carcinoma are still unknown.
Genomic instability involving chromosomal or single nucleotide polymorphism may
represent the cause of tumorigenesis in liver cancer. Somatic recurrently
mutated genes such as FGF, ARID1A, CTNNB1, TP53, and TERT with implicated
signalling pathways such as PI3K-AKT-mTOR, BntB-catenin, and JAK/STAT have been
identified as the main drivers of hepatocellular carcinoma development. The
main risk factors for the development of liver cancer are long-term infection
with the hepatitis B virus, hepatitis C virus, hepatitis D virus, nonalcoholic
steatohepatitis, alcoholic cirrhosis, autoimmune hepatitis, type 2 diabetes,
obesity, and consumption of food contaminated with alpha toxin B1. Gender,
geographic region, and age may be associated with the occurrence of liver
cancer (Gao et al., 2022).
The development of a liver tumour and
progression to hepatocellular carcinoma is a process that consists of several
steps where different etiologies of hepatocellular carcinoma lead to continuous
cycles of hepatocyte damage-regeneration. Cycles of damage-death-regeneration
of hepatocytes cause collagen accumulation, which is thought to contribute to
fibrosis. This leads to a cirrhotic condition after a long time of repetition.
The cirrhotic state of the liver is a pathological condition whose lesions tend
to progress to a premalignant state that generates dysplastic nodules. Then,
dysplastic nodules progress to hepatocellular carcinoma, whose cells invade the
surrounding stroma and, in certain cases, generate metastases�molecular
mechanisms of different cellular changes and changes in the liver
microenvironment. One of the first intrusive changes during hepatotumorigenesis
is the shortening of telomeres, which causes the loss of control of cell cycle
checkpoint regulation, which affects the proliferation of hepatocytes (Bisteau et al., 2014).
In 90% of human hepatocellular carcinomas,
during the transition of premalignant lesions to hepatocellular carcinoma,
there is a rapid reversal of telomerase activation and regulation of telomerase
reverse transcriptase. Also, the essential fibrotic state can create a
microenvironment where cytokines secreted by infiltrating immune cells and
myofibroblasts will select hepatocytes with mutations to survive and clone
themselves, leading to tumour development. During the development of liver
cancer, there are changes in several molecular pathways that are involved in
the regulation of the cell cycle, cell proliferation, immune response, and
metabolism. Intracellular signalling induced by dysfunction of tumour
suppressors or oncogenes is considered to be the most critical mechanism for
the development of liver tumours that improves the survival of tumour cells and
stimulates the progression of the cell cycle of tumour cells, as well as in
other types of cancer (Bisteau et al., 2014).
Sharing Needles with Other People
Sharing
needles most often causes the transmission of the hepatitis C virus and
hepatitis B virus, which leads to liver disease (King & Strony, n.d.). In addition, sharing equipment for drug preparation also leads
to the transmission of hepatitis C virus (Hagan et al., 2001).
Doing Tattoos or Piercings with
Non-Sterile Tools
Hepatitis B
virus and hepatitis C virus are associated with tattooing. From 5% to 30% is
the risk of transmission of the hepatitis B virus after a single needlestick
injury from an infected person, while the risk of transmission of the hepatitis
C virus is from 3% to 7%. Young people need to be educated to avoid non-sterile
tattooing environments and prevent the potential transmission of the hepatitis
virus. In addition, using sterile equipment for tattooing should be promoted in
prisons (Cohen, 2021). Piercing is also associated with an increased risk of
transmission of hepatitis B and C viruses (Yang et al., 2015).
Unprotected Sexual Intercourse
Hepatitis C
virus is rarely transmitted through heterosexual intercourse with a regular
partner. At the same time, the risk increases slightly with multiple
heterosexual partners. However, the transmission of hepatitis C in men who have
intercourse with men is well recognized, especially in men who engage in
high-risk sex (Butler et al., 2016). In addition, unprotected sexual intercourse increases the risk
of hepatitis B virus transmission. In the United States in 2008, 50% of acute
hepatitis B virus infections were attributed to unprotected sexual intercourse (Roberts et al., 2021).
Symptoms of Liver Disease
Symptoms of
this liver disease vary greatly depending on the type and underlying cause (Mehta & Reddivari, 2021). However, several common symptoms of liver disorders are as
follows (Lopes & Samant, 2021); (Kushner, 2024):
a.
Abdominal
pain (especially in the upper right side).
b.
Nausea and
vomiting.
c.
Decreased
appetite.
d.
They have
decreased sexual desire.
e.
Change in
stool colour to pale or black.
f.
She had
jaundice.
g.
Ascites or
the stomach is swollen and filled with fluid.
h.
The colour of
the urine becomes dark.
i.
The skin
becomes itchy and bruises quickly.
How to Prevent Liver Disease
����������� Liver
disease can be prevented by maintaining personal hygiene and adopting a healthy
lifestyle as best as possible (Bhadoria et al., 2023). Several ways that can be done to prevent liver disorders are as
follows:
a.
Maintain
ideal body weight.
Maintaining a
healthy weight reduces the risk of developing liver diseases such as NAFLD. Fat
accumulation in hepatocytes is associated with obesity, dyslipidemia, type 2
diabetes, and arterial hypertension (Romero-G�mez et al., 2023).
b.
a healthy
diet with balanced nutrition.
As already
mentioned, a healthy diet rich in fibre from fruits and vegetables, cereals,
and tea reduces the risk of developing liver disease, while red meat, poultry,
and reduced intake of cheese increase the risk (Guo et al., 2022).
c.
Carry out
hepatitis vaccination.
Hepatitis B virus vaccine is
effective in preventing vertical transmission of hepatitis B when a three- or
four-dose vaccination schedule is completed at birth and in early childhood,
which prevents further transmission of the virus, liver cirrhosis, and
hepatocellular carcinoma. Therefore, the hepatitis B virus vaccine represents
the first vaccine for cancer prevention (Flores et al., 2022). The Hepatitis A vaccine is recommended for people at high risk
of infection with the virus (Bell, 2022). Due to the genetic diversity of the hepatitis C virus, no
effective vaccine against the hepatitis C virus has yet been developed.
However, several vaccine candidates under investigation have shown promising
first results (Manne et al., 2021).
d.
Limit
consumption of alcoholic drinks.
Consuming more than 11.5
� 3.3 standard units per week (8 g of alcohol standard unit) leads to a
significant increase in the risk of liver disease (Moon et al., 2023). Even a shallow level of alcohol consumption increases the risk
of mortality caused by cirrhosis; in men, and in men, 12 g of alcohol per day.
With an increased amount of alcohol, there is a sudden increase in the risk of
mortality due to cirrhosis. The risk of mortality from cirrhosis in women is 14
times higher when they consume 60 g of alcohol per day. In men, it is 14 times
higher for the same amount of alcohol compared to women and men who do not
consume alcohol (Prince et al., 2023).
e.
Maintain
cleanliness of the surrounding environment.
Keeping your environment clean
reduces the risk of infection with viruses such as hepatitis viruses and
exposure to harmful chemical substances that can lead to liver disease (Beier & Arteel, 2021).
f.
Exercise
regularly
Regular
exercise reduces the risk of type 2 diabetes, obesity, and other metabolic
conditions known to be risk factors for liver disease (Thyfault & Bergouignan, 2020).
g.
Take
medicines according to the doctor's recommendations.
Prevention of kidney disease is
very important because when liver cirrhosis develops, no therapy can reverse
the course of the disease (Bhadoria et al., 2023). In addition to pharmacological drug therapy, certain herbal
preparations have shown potential for treating liver disease. However, further
research is needed that will include a large sample to determine the exact
effect of these preparations (Mancak et al., 2024).
h.
Wash your
hands before processing food, eating, and using the toilet.
Maintaining personal hygiene is
very important for the prevention of liver disease because through
contamination with the faeces of an infectious person, the hepatitis virus can
be transmitted, which will lead to inflammation of the liver in a mild or severe
form (Mehta & Reddivari, 2021).
i.
Do not share
needles and personal items with other people
Sharing needles among doga users,
as well as shared drug preparation equipment, increases the risk of hepatitis C
virus transmission (Hagan et al., 2001). Also, using an unsterilized needle for tattooing or piercing
increases the risk of transmission of the hepatitis virus (Tohme & Holmberg, 2012).
j.
We are having
safe sexual relations, such as not having multiple partners and using
protection.
As already noted, responsible
sexual behaviour reduces the risk of hepatitis virus transmission. At the same
time, unprotected sex with multiple partners increases the risk (K�nzler-Heule et al., 2021).
k.
Consult a
doctor first before consuming certain medicines (especially those that are
toxic to the liver) or herbal medicines.
Pharmaceutical
drugs and herbs are medicinal in one dose, while other doses can be toxic. In
addition, the interaction between drugs and herbs can reduce the toxicological
or pharmacological effects of the components. In long-term therapies,
interactions between components can complicate drug dosing (Hussain, 2011)
Liver disease
is a medical condition that can disrupt the body's metabolic processes.
Therefore, this health problem needs to be treated appropriately so as not to
cause serious complications.
Mesenchymal Stem Cell for Liver
Disease
Mesenchymal
stem cells (MSCs) derived from umbilical cord blood hold significant promise
for liver regeneration and recovery of liver function. The liver has a
remarkable ability to regenerate. However, this capacity may be overwhelmed by
severe damage or chronic disease. MSCs have shown potential in preclinical and
clinical studies for their ability to promote tissue repair and modulate immune
responses.
Here is how MSCs from umbilical
cord blood can aid in liver recovery:
1.
Differentiation:
MSCs can differentiate into various cell types, including hepatocytes, the
liver's functional cells. When injected into the damaged liver, these MSCs can
integrate into the tissue and contribute to the regeneration of hepatocytes.
2.
Immunomodulation:
MSCs possess immunomodulatory properties, meaning they can regulate the immune
response. In liver diseases where inflammation plays a significant role in
tissue damage, MSCs can help by reducing inflammation and promoting tissue
healing.
3.
Paracrine
Effects: MSCs secrete various growth factors, cytokines, and other molecules
that can stimulate tissue repair and regeneration. These factors can promote
the proliferation of existing hepatocytes, enhance angiogenesis (formation of
new blood vessels), and inhibit cell death.
4.
Anti-fibrotic
Effects: In chronic liver diseases like cirrhosis, excessive scar tissue
formation (fibrosis) can impair liver function. MSCs have been shown to have
anti-fibrotic effects, potentially slowing down or reversing fibrosis
progression.
5.
Safety and
Availability: MSCs derived from umbilical cord blood are considered safe and
pose minimal risk of immune rejection or tumour formation. Additionally,
umbilical cord blood is a readily available and non-invasive source of MSCs,
making them more accessible for therapeutic use.
����������� Clinical
trials investigating the use of MSCs for liver diseases, including cirrhosis
and acute liver failure, have shown promising results in terms of safety and
efficacy. However, further research is needed to optimize the delivery methods,
dosing regimens, and patient selection criteria for MSC-based therapies in
liver disease. Overall, MSCs from umbilical cord blood offer a potential
therapeutic strategy for promoting liver regeneration and recovery of liver
function.
METHOD
This research uses a qualitative descriptive
method with a case study. The Application of Mesenchymal Stem Cells for Liver
function recovery offers the potential to modify the natural recovery of
degeneration using stem cell-based technology. The qualitative method was
chosen because this research aims to explain and analyze the effectiveness of
combination stem cell therapy of Mesenchymal Stem Cells for liver function
recovery.
This research was carried out at the Celltech
Stem Cell Center Laboratory and Banking with the Vinski Regenerative Center,
the leading stem cell therapy clinic from the Celltech Stem Cell Center
laboratory located at Vinski Tower, Jl. Ciputat Raya No. 22 A Pondok Pinang,
South Jakarta, Indonesia 12310.
This study involved two male patients aged 44
and 71 years who experienced Liver Disease with various complaints such as
abdominal pain (especially in the upper right side), nausea and vomiting,
decreased appetite, decreased sexual desire, and change in stool colour to pale
or black, suffering from jaundice, ascites or the stomach is swollen and filled
with fluid, the colour of the urine becomes dark, and the skin becomes itchy
and bruises quickly.
Each patient is researched using comparative
literature studies and based on laboratory results and each patient's
complaints. Then, each patient undergoes stem cell therapy, injected repeatedly
over a certain period, which can be 3 to 4 repetitions in 12 months. Patient
data is collected periodically and recorded in a notation book containing
personal data and health history.
Several descriptive data collection techniques
exist, including interviews and observation. All participants provided baseline
data, including demographic information and disease characteristics.
RESULTS AND DISCUSSION
Dose
Patients are
treated with live stem cells maintained at CELLTECH's Stem Cell and Banking
Laboratory, and therapy is performed at the Vinski Regenerative Center clinic.
Stem cells are stored in cryo tanks at -1900 Celsius (190 degrees below
freezing), which is done in a "closed system" or "open
system." Closed systems run independently of human operations and are
fully automated. In contrast, open systems use human operators to adjust the
process as necessary. Closed systems are also referred to as quantum processes.
This system is considered more efficient and sterile than an open system
because it operates automatically in an isolated system and is separated from
human intervention. The main concentration of stem cells comes from the
umbilical cord and umbilical cord blood. Stem cells are stored in vials
containing 20 million cells or more. The administration of stem cells for
therapeutic purposes depends on the type and severity of the disease, as this
determines the number of stem cells required.
The stem cell
dose is calculated by measuring the patient's body weight (in kilograms) and
multiplying it by a factor of one million. For example, the dose for a person
weighing 70 kg is 70 million stem cells (70 x 1,000,000). The allogeneic nature
of stem cells allows the replacement and restoration of damaged cells at the
target site of recovery (Hussain, 2011). The dosage is also influenced by the number of cells damaged and
needing to be restored. The quality of recovery depends on the dose. For
example, a pack containing 20 million stem cells may have minimal effects. At
the same time, a higher dose will be more effective for severe conditions.
Patient
progress is monitored three months after each round of stem cell therapy to
determine treatment efficacy. The treatment used for this case study is
consistent with the success of stem cell treatment for diseases such as
Prader-Willi syndrome, autism, stroke, diabetes, and several others. The theory
underlying this case study is that stem cells have regenerative properties that
can rejuvenate and replace damaged cell tissue, and because of their allogenic
nature, stem cells can be applied to any part of the body.
Case
treatment
To better
understand the reviewed theory, a clinical trial was conducted to test its
effectiveness. Two cases were selected from patients who have undergone liver
treatments using the MSCUC Stem Cell, with the following results.
Patient A
Sex: Male
Age: 44 years.
Diagnosis: Somatomedin Deficiency
Syndrom
Main complaint: Hiperkolesterol
and fatty liver
Laboratory Progress: Within the
five injections.
Table 1. Result of Laboratory Test
for Patient A
|
Laboratory Test
|
Result
# 1
|
Result
# 2
|
Result
# 3
|
Result
# 4
|
Result
# 5
|
Ref. Value
|
Unit
|
|
SGOT
|
29
|
28
|
23
|
22
|
19
|
5-40
|
U/l
|
|
SGPT
|
82
|
75
|
62
|
36
|
24
|
7-56
|
U/l
|
|
Gamma-GT
|
85
|
80
|
70
|
49
|
34
|
˂38
|
U/l
|
Patient B�
Sex: Male
Age: 71 years
Diagnosis: Somatomedin
Deficiency Syndrom
Main complaint: Fatty liver
Laboratory Progress:� After six times injections.
Table 2. Result of Laboratory Test
for Patient B
|
Laboratory Test
|
Result
# 1
|
Result
# 2
|
Result
# 3
|
Result
# 4
|
Result
# 5
|
Ref. Value
|
Unit
|
|
SGOT
|
33
|
30
|
29
|
29
|
27
|
5-40
|
U/l
|
|
SGPT
|
55
|
53
|
50
|
49
|
44
|
7-56
|
U/l
|
|
Gamma-GT
|
-
|
-
|
-
|
-
|
-
|
˂38
|
U/l
|
Follow up
����������� Recovery of Liver Function with Stem
Cell therapies and regenerative medicine is kindly suggested to enjoy everyday
life and be aware of maintaining a healthy liver condition by inspecting the
normal health state at least every six months.
Patient
comments and physical health
����������� Based on research on patients with
liver function disorders at our clinic, almost all of them experienced
abdominal pain, nausea, and vomiting, decreased appetite, decreased sexual
desire, change in stool colour to pale or black, suffering from jaundice,
ascites or stomach is swollen and filled with fluid, the colour of the urine
becomes dark, the skin becomes itchy and bruises quickly. Then, each patient is
injected with stem cells. After three months, patient monitoring and evaluation
are carried out. The spinal repair process varies. Some patients feel the
effects immediately after one injection, and some only feel the effects of stem
cell therapy after one month. The symptoms the patient felt before therapy
gradually recovered after the stem cell injection. The patient could return to
his activities, and the pain he complained of gradually disappeared.
����������� Patient complaints before treatment
and comments after treatment are recorded and well documented. Despite the age
difference, patient A suffers from a more severe illness than Patient B.
Patient A is 44 years old. In comparison, patient B is 76 years old, and based
on laboratory tests, the SGOT and SGPT are within normal limits; only the liver
is covered. by fat and shows some anomalies that are felt by some inability to
exercise daily. With patient A, in addition to fatty liver, Somatomedin
Deficiency Syndrome was detected. This makes exercise problems almost
impossible. Patient A's test results showed that the problem was not too
serious. Hence, the patient quickly felt tired when exercising.
CONCLUSION
Mesenchymal stem cells (MSCs) derived
from umbilical cord blood offer a promising therapeutic avenue for the recovery
of liver function in patients with liver disease. Preclinical studies have
demonstrated the ability of umbilical cord blood-derived MSCs to promote liver
regeneration, attenuate fibrosis, and improve overall liver function. Moreover,
clinical trials have provided encouraging evidence of the safety and efficacy
of MSC transplantation in patients with liver cirrhosis and acute liver failure.
The unique properties of umbilical cord blood-derived MSCs, including their
multipotent differentiation capacity, immunomodulatory effects, and paracrine
signalling, make them an attractive candidate for liver regeneration therapy.
However, challenges such as optimizing dosing regimens, timing of
administration, and long-term monitoring need to be addressed to maximize the
therapeutic potential of MSC-based treatments. Future research should focus on
elucidating the underlying mechanisms of action of MSCs in liver regeneration,
optimizing transplantation protocols, and conducting large-scale clinical
trials to establish the long-term safety and efficacy of MSC-based therapies. Additionally, efforts to
standardize manufacturing processes and develop quality control measures for
MSC products are essential for ensuring the reproducibility and scalability of
these therapies. Overall, MSCs derived from umbilical cord blood hold great
promise as a regenerative therapy for liver diseases and have the potential to
significantly improve outcomes and quality of life for patients in need of
liver transplantation or those with advanced liver disease. Continued research
and clinical development in this field is warranted to realize the full
therapeutic potential of MSC-based treatments for liver regeneration.
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