title: Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver.
abstract: Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End-Stage Liver Disease (ρ = -0.582, P < 0.001) and Child's scores (P < 0.038). BMs of cirrhosis patients with higher Model of End-Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin-1β (P = 0.004), tumor necrosis factor-α (P = 0.040), and interferon-γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell-derived factor 1 (P = 0.03) compared to those with lower Model of End-Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction.
  
  
  
  Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273-1288).
authors.affiliation: Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Chhagan
authors.initials: C
authors.lastname: Bihari
authors.affiliation: Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Lovkesh
authors.initials: L
authors.lastname: Anand
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Sheetalnath
authors.initials: S
authors.lastname: Rooge
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Saxena
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Shubham
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.lastname: Sukriti
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Nirupma
authors.initials: N
authors.lastname: Trehanpati
authors.affiliation: Department of Clinical Research, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Guresh
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Liver Transplant & Hepato-pancreatico-biliary Surgery, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Viniyendra
authors.initials: V
authors.lastname: Pamecha
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Shvetank
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Rastogi
authors.affiliation: Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India. shivsarin@gmail.com.|Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India. shivsarin@gmail.com.
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sarin
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000473:pathology*; D058625:End Stage Liver Disease; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D055153:Stem Cell Niche; D013234:Stem Cells / Q000473:pathology*