Cellular Therapy For Cirrhosis

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Cellular Therapy For Cirrhosis

Therapies with the potential to substitute for liver transplantation or bridge the patient awaiting transplantation are required. Liver cell transplantation (LCT), an experimental procedure designed to reconstitute the liver mass with functional hepatocytes, is based on transplantation of isolated hepatocytes from a cadaver or from a liver portion from a living donor 75. This experimental procedure has been successfully used in patients to correct certain metabolic disorders 75. Another experimental procedure involves transplantation of hematopoietic bone marrow (BM) progenitor cells or adipose-tissue derived mesenchymal cells 76. Transplantation of fetal hepatocytes has also been considered as an alternative treatment 77.

Liver cell transplantation (LCT) has been attempted in patients with acute liver failure, chronic liver disease with end-stage cirrhosis, and children with metabolic disease 75. To date, the best outcome of allogenic hepatocyte transplantation was reported for treatment of acute liver failure. In this case, allogenic infusion of hepatocytes is aimed to provide rapid metabolism of liver toxins and stabilization of hemodynamic parameters. Thus, in 20% of patients LCT of hepatocytes from cadaver livers resulted in recovery without solid organ transplant, and in 30% bridged patients to liver transplantation 78–80. Some progress has been made in correction of metabolic diseases. According to their etiology, metabolic disorders could be divided in two groups, inherited clotting factor deficiencies and metabolic deficiencies 75. Since metabolic deficiencies are often associated with the severe damage to hepatocytes, transplanted hepatocytes have a growth advantage over recipient hepatocytes. Under these conditions, donor hepatocytes have a selective pressure and LCT has been reported in patients to correct ornithine trans-carbamylase (OTC) deficiency, α-1-anti-trypsin deficiency, glycogen storage disease type Ia, infantile Refsum’s desease, factor VII deficiency, bile salt export protein deficiency, and Crigler-Najjar syndrome type 1 75, 81, 82.

Purified hepatocytes are infused in patients via the portal vein or are injected into the spleen 83. On average, only 30% of hepatocytes survive transplantation. Therefore, successful engraftment often depends on the number of infused hepatocytes 83. Infusion of hepatocytes into the portal vein causes transient portal hypertension, and must be combined with pharmacological disruption of endothelial integrity required for hepatocyte extravazation 84. Hepatocytes do not tolerate cryopreservation well and lose expression of adhesion molecules, which play an important role in hepatocyte extravasation and engraftment between the host hepatocytes 84. In addition, cryopreservation further decreases the viability of hepatocytes by 30% 85, 86. Immunological rejection of hepatocytes requires prolonged immunosuppressive therapy in patients suitable for LCT 87. Identification and characterization of hepatocyte progenitor/stem cells and their differentiation into functionally mature liver cells is an evolving goal for the stem cell therapy.

The improvement of liver function following the transplantation of hematopoietic progenitors in mice and rats provided the basis for clinical trials. To date, 11 clinical trials with BM-derived cells have been conducted 77. Clinical studies with transplantation of autologous CD133+ BM cells in patients have been reported to stimulate liver regeneration, as demonstrated by a reduction of bilirubin, increased albumin, and improved coagulopathy 88. Similar to that, autologous infusion of CD34+ blood cells, or even concentrated monocytes, improved biochemical parameters and stimulated liver regeneration 89. While transplantation of hematopoietic progenitors appeared beneficial in patients, the mechanism of their action remains controversial and may not reflect the generation of BM-derived hepatocytes. Such improvement may result from release of cytokines and growth factors by transplanted hematopoietic cells, or occur due to infusion of scar-resorbing monocytes. In concordance with this observation, treatment with granulocyte-colony stimulating factor (G-CSF) was used to mobilize the BM cells and demonstrated a positive effect in patients with alcoholic steatohepatitis 90.

Mesenchymal stem cells serve as another attractive target for the liver stem cell therapy. Although infusion of MSCs often results in attenuation or improvement of liver disease, current studies have not provided definitive evidence that MSCs have a capability to differentiate into functional hepatocytes in vivo 91–95. In turn, these improvements could be attributed to the secretion of soluble factors by MSCs, rather then transdifferentiation into hepatocytes. In concordance with this notion, injection of MSC-derived conditioning media into a liver-assist device can prevent hepatocyte apoptosis and increase their proliferation. Moreover, recent studies have raised a safety question of MSCs transplantation, demonstrating that MSCs can give rise to fibrogenic myofibroblasts in mice in response to liver injury. BM-derived MSCs contributed to the development of liver fibrosis in chimeric mice that received bone marrow transplantation with the enriched BM mesenchymal fraction, and subjected to the CCl4-liver injury 43. Taken together, both hematopoietic and mesenchymal stem cells demonstrated a limited contribution to hepatocyte replenishment, but may stimulate liver function by providing soluble growth factors or cytokines 41, 98, 99

A few clinical trials have been performed in patients with the cirrhosis caused by hepatitis B, hepatitis C, alcohol, or cryptogenic. These patients were transplanted with autologous MSCs harvested from the iliac crest. The tested parameters (albumin, creatinine) demonstrated a modest but significant improvement without severe adverse effects, suggesting that MSCs injection might be useful for the treatment of end-stage liver disease with satisfactory tolerability 100. In a different clinical trial, MSCs were used in patients with decompensated cirrhosis. All patients showed good tolerance and decreased Model for end-stage liver disease (MELD) scores, and improvement in albumin production and liver function after six month of follow up.

I could go on and on about this stuff. Anybody going through any treatments or looking into these types of treatments?

[Lynn K]

Never heard anything about this can you provide your source link?

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HellO, Lynn K, it's been awhile since I've been back here but I'm back for a reason like anybody else who is trying to find more ways than one for more treatments, healings of anykind, I have to keep searching, I have to keep fighting for some healthier living if I want to extend my life just a lil longer for my family, I'm only 44 and still got lots of life & spark in me to light up our world while I'm still here. So yeah, please reply back with anything, let's get this thing going and maybe everyone here will chime in with more suggestions, advise, more research studies, cures, clinical trials, because let me tell ya, there sure are awhole lot of research clinical trials going on too, I have that link if anybody wants it. Well, hopefully this has helped someone, ya'll have a good morning & day, peace.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086317/

Anti-fibrogenic Strategies and the regression of fibrosis