title: Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development.
abstract: Chronic liver disease is characterized by the liver enrichment of myeloid dendritic cells (DCs). To assess the role of disease on myelopoiesis, we utilized a systems biology approach to study development in liver-resident cells expressing stem cell marker CD34. In patients with endstage liver disease, liver CD34+ cells were comprised of two subsets, designated CD34+CD146+ and CD34+CD146-, and hematopoietic function was restricted to CD34+CD146- cells. Liver CD34 frequencies were reduced during nonalcoholic steatohepatitis (NASH) and chronic hepatitis C virus (HCV) compared to alcohol liver disease (ALD), and this reduction correlated with viral load in the HCV cohort. To better understand the relationship between liver CD34+CD146+ and CD34+CD146- subsets and any effects of disease on CD34 development, we used gene expression profiling and computational modeling to compare each subset during ALD and HCV. For CD34+CD146+ cells, increased expression of endothelial cell genes including von Willebrand factor, VE-cadherin, and eNOS were observed when compared to CD34+CD146- cells, and minimal effects of ALD and HCV diseases on gene expression were observed. Importantly for CD34+CD146- cells, chronic HCV was associated with a distinct "imprint" of programs related to cell cycle, DNA repair, chemotaxis, development, and activation, with an emphasis on myeloid and B lymphocyte lineages. This HCV signature was further translated in side-by-side analyses, where HCV CD34+CD146- cells demonstrated superior hematopoietic growth, colony formation, and diversification compared to ALD and NASH when cultured identically. Disease-associated effects on hematopoiesis were also evident by phenotypic alterations in the expression of CD14, HLA-DR, and CD16 by myeloid progeny cells.
  
  
  CONCLUSIONS
  Etiology drives progenitor fate within diseased tissues. The liver may be a useful source of hematopoietic cells for therapy, or as therapeutic targets.
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Velazquez
authors.forename: Luke S
authors.initials: LS
authors.lastname: Uebelhoer
authors.forename: Manoj
authors.initials: M
authors.lastname: Thapa
authors.forename: Chris C
authors.initials: CC
authors.lastname: Ibegbu
authors.forename: Cynthia
authors.initials: C
authors.lastname: Courtney
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bosinger
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Magliocca
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalman
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D051929:CD146 Antigen / Q000032:analysis; D019070:Cell Lineage; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000166:cytology*; D065626:Non-alcoholic Fatty Liver Disease / Q000503:physiopathology; D049490:Systems Biology; D019562:Viral Load
chemical_list: D018952:Antigens, CD34; D051929:CD146 Antigen; C497902:MCAM protein, human