In Case You Missed ItLancet Gastroenterology & Hepatology
Volume 3, No. 1, p3–5, January 2018
DOI: http://dx.doi.org/10.1016/S2468-1253(17)30359-X
Comment
Haemopoietic stem cell therapy in cirrhosis: the end of the story?
Nicolas Lanthier
Chronic liver diseases can lead to cirrhosis, characterised by fibrous septa dissecting the liver parenchyma, affecting both liver function (due to reduced functional mass) and normal intrahepatic venous pressure (due to increased stiffness). Some specific treatments for the underlying causes of the disease exist, such as antiviral treatment for hepatitis B or C virus infection, alcohol abstinence for alcohol-related liver disease, or weight loss strategies for metabolic non-alcoholic fatty liver disease, whereas other causes remain difficult to treat (like genetic disorders or autoimmune problems). Despite existing strategies, some patients still progress towards end-stage liver disease and its associated complications, including ascites, peritonitis, variceal bleeding, or hepatocellular carcinoma. No treatment is available to specifically target fibrosis and cirrhosis, and liver transplantation remains the only curative option. To avoid progression towards end-stage liver disease ultimately requiring a rescue transplantation—which is not devoid of disadvantages (donor organ shortage, challenging surgery, and lifelong immunosuppression)—many researchers are investigating strategies to restore liver functionality.
Cell therapy is an emerging approach being tested in this setting. Hepatocytes are the principal cells of the liver parenchyma and are responsible for maintaining liver function. They can originate from three sources.1 In a normal liver, hepatocytes themselves can proliferate to restore the functional liver mass, a mechanism that could be compromised in cirrhosis. Second, the liver contains liver progenitor cells that can also proliferate and differentiate into hepatocytes. However, in some circumstances, this differentiation does not occur.2 Finally, blood-derived stem cells can infiltrate the liver and become hepatocytes, although the participation of this process in liver regeneration is poorly understood.3
In a randomised controlled trial,4 Philip Newsome and colleagues investigated whether granulocyte colony-stimulating factor (G-CSF) with or without haemopoietic stem cell transplantation could improve liver function and reduce complications related to liver cirrhosis. Indeed, it has been proposed that bone-marrow-derived stem cells can engraft the diseased liver and differentiate toward hepatocytes, while G-CSF can stimulate bone marrow cell recruitment and liver progenitor cell proliferation.5, 6 This study is of interest because of its rigorous design and evaluation, and it adds to the evidence from numerous case reports and small studies that have suggested a beneficial effect from both strategies on liver function and patient survival. Unfortunately, in this trial, neither G-CSF alone nor combined with three autologous stem-cell infusions (harvested from the peripheral blood) into patients' peripheral veins improved liver function as assessed by MELD score, which was calculated by a routine blood test, after 3 months. Complications of cirrhosis were even more common in the combined therapy group. Finally, liver stiffness evaluation by transient elastography did not show any effect of the treatment.4
Notably, these results are in line with those from a previous randomised controlled trial7—the only trial on this subject to be regarded as a high-quality study8—which also found that G-CSF and bone-marrow-derived cells injected into the hepatic artery had no effect in the context of severe decompensated alcoholic cirrhosis. The new data provided by Newsome and colleagues' study show that even in liver disease with relatively low levels of inflammation, the treatment stimulus is not sufficient to promote liver regeneration and subsequent recovery of liver function.
These results highlight the importance of not drawing premature and possibly hazardous conclusions before solid preclinical evidence becomes available and subsequent well conducted clinical trials are done. Future research into potential treatments for cirrhosis should also include a refined assessment of treatment response. First, cell tracking experiments in human beings are needed to establish whether cells infused by the peripheral route or directly injected into the hepatic circulation in the context of portal hypertension really do engraft the liver or not. Studies of the biodistribution of labelled cells in humans could answer this question.9 Second, more specific biomarkers or at least more precise liver imaging to assess fibrosis are probably needed. Patient survival, MELD score, and liver elasticity changes do not seem to be sufficient to detect any therapeutic effect of cell transplantation, if there is one. However, concomitantly, or before such experiments are done, progress is needed in basic research to discover the determining factors explaining why some patients with cirrhosis will have decompensation despite adequate control of the causes of the disease. In this context, predictive baseline patient factors need to be identified, which could originate from several sources. These factors could be from the liver itself (eg, hypoxia, low-grade inflammation, and microscopic thrombotic events), and assessment of the liver tissue before and after treatment to characterise regenerative pathways or side-effects should provide important data.10 Indeed, it could simply be the case that if the diseased liver itself is not able to develop its own efficacious repopulation mechanisms, external strategies will also fail. Alternatively, factors originating from outside the liver, such as from the gut (eg, altered barrier function and microbiome dysregulation), the muscles (characterised by sarcopenia), or the inflamed adipose tissue in obesity, could also play an important part. Future trials to address these questions in an era of emerging liver disease epidemics will be of great interest. Ideally, future trials should target one cause of cirrhosis at a time, given that the mechanisms could be different depending on the cause of the liver disease. For example, chronic active hepatitis C, which characterised some patients in Newsome and colleagues' trial, might not remain a problem because of existing efficacious viral eradication approaches, making cirrhosis due to non-alcoholic fatty liver disease the primary cause of end-stage liver disease.
In conclusion, the robust data provided by Newsome and colleagues do not support G-CSF with or without haemopoietic stem-cell infusion having any effect on liver function in patients with cirrhosis. With liver regeneration and anti-fibrotic strategies remaining fascinating subjects of research, further efforts will be needed to shed light on the complexity and interconnectedness of regeneration and cirrhosis before novel effective clinical strategies can be developed to overcome the problem of a failing liver.
Cell therapy is an emerging approach being tested in this setting. Hepatocytes are the principal cells of the liver parenchyma and are responsible for maintaining liver function. They can originate from three sources.1 In a normal liver, hepatocytes themselves can proliferate to restore the functional liver mass, a mechanism that could be compromised in cirrhosis. Second, the liver contains liver progenitor cells that can also proliferate and differentiate into hepatocytes. However, in some circumstances, this differentiation does not occur.2 Finally, blood-derived stem cells can infiltrate the liver and become hepatocytes, although the participation of this process in liver regeneration is poorly understood.3
In a randomised controlled trial,4 Philip Newsome and colleagues investigated whether granulocyte colony-stimulating factor (G-CSF) with or without haemopoietic stem cell transplantation could improve liver function and reduce complications related to liver cirrhosis. Indeed, it has been proposed that bone-marrow-derived stem cells can engraft the diseased liver and differentiate toward hepatocytes, while G-CSF can stimulate bone marrow cell recruitment and liver progenitor cell proliferation.5, 6 This study is of interest because of its rigorous design and evaluation, and it adds to the evidence from numerous case reports and small studies that have suggested a beneficial effect from both strategies on liver function and patient survival. Unfortunately, in this trial, neither G-CSF alone nor combined with three autologous stem-cell infusions (harvested from the peripheral blood) into patients' peripheral veins improved liver function as assessed by MELD score, which was calculated by a routine blood test, after 3 months. Complications of cirrhosis were even more common in the combined therapy group. Finally, liver stiffness evaluation by transient elastography did not show any effect of the treatment.4
Notably, these results are in line with those from a previous randomised controlled trial7—the only trial on this subject to be regarded as a high-quality study8—which also found that G-CSF and bone-marrow-derived cells injected into the hepatic artery had no effect in the context of severe decompensated alcoholic cirrhosis. The new data provided by Newsome and colleagues' study show that even in liver disease with relatively low levels of inflammation, the treatment stimulus is not sufficient to promote liver regeneration and subsequent recovery of liver function.
These results highlight the importance of not drawing premature and possibly hazardous conclusions before solid preclinical evidence becomes available and subsequent well conducted clinical trials are done. Future research into potential treatments for cirrhosis should also include a refined assessment of treatment response. First, cell tracking experiments in human beings are needed to establish whether cells infused by the peripheral route or directly injected into the hepatic circulation in the context of portal hypertension really do engraft the liver or not. Studies of the biodistribution of labelled cells in humans could answer this question.9 Second, more specific biomarkers or at least more precise liver imaging to assess fibrosis are probably needed. Patient survival, MELD score, and liver elasticity changes do not seem to be sufficient to detect any therapeutic effect of cell transplantation, if there is one. However, concomitantly, or before such experiments are done, progress is needed in basic research to discover the determining factors explaining why some patients with cirrhosis will have decompensation despite adequate control of the causes of the disease. In this context, predictive baseline patient factors need to be identified, which could originate from several sources. These factors could be from the liver itself (eg, hypoxia, low-grade inflammation, and microscopic thrombotic events), and assessment of the liver tissue before and after treatment to characterise regenerative pathways or side-effects should provide important data.10 Indeed, it could simply be the case that if the diseased liver itself is not able to develop its own efficacious repopulation mechanisms, external strategies will also fail. Alternatively, factors originating from outside the liver, such as from the gut (eg, altered barrier function and microbiome dysregulation), the muscles (characterised by sarcopenia), or the inflamed adipose tissue in obesity, could also play an important part. Future trials to address these questions in an era of emerging liver disease epidemics will be of great interest. Ideally, future trials should target one cause of cirrhosis at a time, given that the mechanisms could be different depending on the cause of the liver disease. For example, chronic active hepatitis C, which characterised some patients in Newsome and colleagues' trial, might not remain a problem because of existing efficacious viral eradication approaches, making cirrhosis due to non-alcoholic fatty liver disease the primary cause of end-stage liver disease.
In conclusion, the robust data provided by Newsome and colleagues do not support G-CSF with or without haemopoietic stem-cell infusion having any effect on liver function in patients with cirrhosis. With liver regeneration and anti-fibrotic strategies remaining fascinating subjects of research, further efforts will be needed to shed light on the complexity and interconnectedness of regeneration and cirrhosis before novel effective clinical strategies can be developed to overcome the problem of a failing liver.
Voisin/Phanie/Science Photo Library
References
- Lanthier, N, Rubbia-Brandt, L, and Spahr, L. Liver progenitor cells and therapeutic potential of stem cells in human chronic liver diseases. Acta Gastroenterol Belg. 2013; 76: 3–9
- Dubuquoy, L, Louvet, A, Lassailly, G et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut. 2015; 64: 1949–1960
- Alison, MR, Poulsom, R, Jeffery, R et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000; 406: 257
- Newsome, PN, Fox, R, King, AL et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. (published online Nov 7.)Lancet Gastroenterol Hepatol. 2017;
- Forbes, SJ and Newsome, PN. New horizons for stem cell therapy in liver disease. J Hepatol. 2012; 56: 496–499
- Spahr, L, Lambert, JF, Rubbia-Brandt, L et al. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology. 2008; 48: 221–229
- Spahr, L, Chalandon, Y, Terraz, S et al. Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial. PLoS One. 2013; 8: e53719
- Moore, JK, Stutchfield, BM, and Forbes, SJ. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther. 2014; 39: 673–685
- Sokal, EM, Lombard, CA, Roelants, V et al. Biodistribution of liver-derived mesenchymal stem cells after peripheral injection in a hemophilia a patient. Transplantation. 2017; 101: 1845–1851
- Lanthier, N, Lin-Marq, N, Rubbia-Brandt, L, Clement, S, Goossens, N, and Spahr, L. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: what is the impact on liver histology and gene expression patterns?. Stem Cell Res Ther. 2017; 8: 88
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