Prospects for Adult Stem Cells in the Treatment of Liver Diseases

Fagoonee, Sharmila; Famulari, Elvira Smeralda; Silengo, Lorenzo; Camussi, Giovanni; Altruda, Fiorella

doi:10.1089/scd.2016.0144

Cited by 10 publications

(14 citation statements)

References 118 publications

(133 reference statements)

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“…MSCs are considered to act through multiple mechanisms to coordinate a dynamic, integrated response to liver inflammation and fibrosis, which prevents the progressive distortion of hepatic architecture. Management of inflammatory patterns is crucial also in case of potential treatment of liver diseases with stem cells[ 32 ]. Adult stem cells have gained in attractiveness over embryonic stem cells for liver cell therapy due to their origin, multipotentiality, and the possibility of autologous transplantation.…”

Section: Activation Of the Innate Immune Response During Nafldmentioning

confidence: 99%

Role of inflammatory response in liver diseases: Therapeutic strategies

Campo¹,

Gallego²,

Grande³

2018

WJH

272

176

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Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus (HCV) infection, and sterile stressors (oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro- or anti-apoptotic. Acute and chronic liver diseases are cytokine-driven diseases as several proinflammatory cytokines (IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

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Section: Activation Of the Innate Immune Response During Nafldmentioning

confidence: 99%

Role of inflammatory response in liver diseases: Therapeutic strategies

Campo¹,

Gallego²,

Grande³

2018

WJH

272

176

View full text Add to dashboard Cite

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“…In this regard, the use of immunotherapy, pancreatic, or Langerhans transplantation, as well as cell therapy, especially the use of stem cells, is being studied . Among the stem cells used in regenerative medicine, we can refer to mesenchymal cells (MSCs) with proven immunomodulatory properties . These immunomodulatory effects of MSCs have been studied in various autoimmune diseases, including T1DM …”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes

Nojehdehi

Soudi

Hesampour

et al. 2018

J of Cellular Biochemistry

201

142

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Exosomes derived from adipose tissue-derived mesenchymal stem cells (AD-MSCs) have immunomodulatory effects of T-cell inflammatory response and reduction of clinical symptoms on streptozotocin-induced of the type-1 diabetes mellitus (T1DM). Beside control group and untreated T1DM mice, a group of T1DM mice was treated with intraperitoneal injections of characterized exosomes derived from autologous AD-MSCs. Body weight and blood glucose levels were measured during the procedure. Histopathology and immunohistochemistry were used for evaluation of pancreatic islets using hemotoxylin and eosin (H&E) staining and anti-insulin antibody. Isolated splenic mononuclear cells (MNCs) were subjected to splenocytes proliferation assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, immunophenotyping of regulatory T cells and cytokines. A significant increase in the levels of interleukin-4 (IL-4), IL-10, and transforming growth factor-β, and a decrease in the levels of IL-17 and interferon-γ in concordance with the significant increase in the Treg cell ratio in splenic MNCs (P < 0.05) was shown in T1DM mice treated with AD-MSC's exosomes as compared to T1DM untreated mice. This amelioration of autoimmune reaction after treatment of T1DM mice with the AD-MSC exosomes was confirmed with a significant increase in islets using H&E staining and Immunohistochemistry analyses. As expected, body weight, blood glucose levels in a survival of T1DM mice treated with AD-MSC's exosomes were maintained stable in comparison to untreated T1DM mice. It can be concluded that AD-MSC's exosomes exert ameliorative effects on autoimmune T1DM through increasing regulatory T-cell population and their products without a change in the proliferation index of lymphocytes, which makes them more effective and practical candidates.

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“…Cell therapy has been mainly conducted in the Gunn rat 9 . The immune-compromised NSG/Ugt1 −/− mice may also offer a platform for in vivo testing of safety and efficacy of human cells 33 . These mice offer the advantage of being lethal, hence better mimicking the human disease, if therapy is not efficiently delivered early after birth.…”

Section: Discussionmentioning

confidence: 99%

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice

Famulari

Navarro-Tableros

Sanchez

et al. 2020

Sci Rep

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Crigler Najjar Syndrome type I (CNSI) is a rare recessive disorder caused by mutations in the Ugt1a1 gene. There is no permanent cure except for liver transplantation, and current therapies present several shortcomings. Since stem cell-based therapy offers a promising alternative for the treatment of this disorder, we evaluated the therapeutic potential of human liver stem cells (HLSC) in immunecompromised NOD SCID Gamma (NSG)/Ugt1 −/− mice, which closely mimic the pathological manifestations in CNSI patients. To assess whether HLSC expressed UGT1A1, decellularised mouse liver scaffolds were repopulated with these cells. After 15 days' culture ex vivo, HLSC differentiated into hepatocyte-like cells showing UGT1A1 expression and activity. For the in vivo human cell engraftment and recovery experiments, DiI-labelled HLSC were injected into the liver of 5 days old NSG/Ugt1 −/− pups which were analysed at postnatal Day 21. HLSC expressed UGT1A1 in vivo, induced a strong decrease in serum unconjugated bilirubin, thus significantly improving phenotype and survival compared to untreated controls. A striking recovery from brain damage was also observed in HLSCinjected mutant mice versus controls. Our proof-of-concept study shows that HLSC express UGT1A1 in vivo and improve the phenotype and survival of NSG/Ugt1 −/− mice, and show promises for the treatment of CNSI.The Crigler Najjar syndrome type I (CNSI; OMIM number 218800) is a rare monogenic disease (0.6 to 1 per 1 000 000 newborns) caused by deficiency in the only enzyme responsible for bilirubin conjugation in the liver, uridine-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 1 . The disease is characterised by severe jaundice (elevated blood levels of bilirubin) since birth and a lifelong risk of bilirubin encephalopathy and death by kernicterus if untreated 2,3 . The current treatment for the disease is intensive phototherapy (PT). However, the clinical management is very difficult since CNSI patients need 10-12 hours/day of PT. In addition, patients respond temporarily to PT, as its effectiveness diminishes with age due to skin thickening and decreased surface/body mass ratio, leading to increased risk of unconjugated bilirubin-induced encephalopathy and permanent brain damage 4 . Liver transplantation can improve the prognosis of inherited metabolic diseases, and is currently the only definitive treatment available for CNSI and other severe liver diseases 5 . However, donor organs are scarce.As an alternative to liver transplantation, cell-based therapy has great potential in the treatment of metabolic liver diseases including CNSI, for the possibility of achieving substitution of diseased hepatic cells and restore damage that may not be possible to correct later in life 23 . Importantly, around 5% of replacement of the total liver mass may improve metabolic disorders, and 10% may normalize liver function 24 . For instance, in humans, infusion of 5% of the liver mass efficiently lowered bilirubin levels in CNSI patients 10,25,26 . In our model, by directly d...

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Prospects for Adult Stem Cells in the Treatment of Liver Diseases

Cited by 10 publications

References 118 publications

Role of inflammatory response in liver diseases: Therapeutic strategies

Role of inflammatory response in liver diseases: Therapeutic strategies

Immunomodulatory effects of mesenchymal stem cell–derived exosomes on experimental type‐1 autoimmune diabetes

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice

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