title: Bone marrow-derived stromal cell therapy in cirrhosis: clinical evidence, cellular mechanisms, and implications for the treatment of hepatocellular carcinoma.
abstract: Current treatment options for hepatocellular carcinoma (HCC) are often limited by the presence of underlying liver disease. In patients with liver cirrhosis, surgery, chemotherapy, and radiation therapy all carry a high risk of hepatic complications, ranging from ascites to fulminant liver failure. For patients receiving radiation therapy, cirrhosis dramatically reduces the already limited radiation tolerance of the liver and represents the most important clinical risk factor for the development of radiation-induced liver disease. Although improvements in conformal radiation delivery techniques have improved our ability to safely irradiate confined areas of the liver to increasingly higher doses with excellent local disease control, patients with moderate-to-severe liver cirrhosis continue to face a shortage of treatment options for HCC. In recent years, evidence has emerged supporting the use of bone marrow-derived stromal cells (BMSCs) as a promising treatment for liver cirrhosis, with several clinical studies demonstrating sustained improvement in clinical parameters of liver function after autologous BMSC infusion. Three predominant populations of BMSCs, namely hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, seem to have therapeutic potential in liver injury and cirrhosis. Preclinical studies of BMSC transplantation have identified a range of mechanisms through which these cells mediate their therapeutic effects, including hepatocyte transdifferentiation and fusion, paracrine stimulation of hepatocyte proliferation, inhibition of activated hepatic stellate cells, enhancement of fibrolytic matrix metalloproteinase activity, and neovascularization of regenerating liver. By bolstering liver function in patients with underlying Child's B or C cirrhosis, autologous BMSC infusion holds great promise as a therapy to improve the safety, efficacy, and utility of surgery, chemotherapy, and hepatic radiation therapy in the treatment of HCC.
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Jeffrey M
authors: JM
authors: Vainshtein
authors: Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
authors: Rafi
authors: R
authors: Kabarriti
authors: Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
authors: Keyur J
authors: KJ
authors: Mehta
authors: Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Genetics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
authors: Jayanta
authors: J
authors: Roy-Chowdhury
authors: Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. Electronic address: cguhamd@gmail.com.
authors: Chandan
authors: C
authors: Guha
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D002459:Cell Fusion; D054338:Cell Transdifferentiation; D055166:Hepatic Stellate Cells / Q000166:cytology; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology / Q000628:therapy; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000528:radiation effects; D008103:Liver Cirrhosis / Q000150:complications / Q000628:therapy*; D008113:Liver Neoplasms / Q000628:therapy*; D008115:Liver Regeneration / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic; D011832:Radiation Injuries / Q000150:complications / Q000628:therapy; D011836:Radiation Tolerance; D016879:Salvage Therapy
chemical_list: D020782:Matrix Metalloproteinases