Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development

Hepatology. 2015 Mar;61(3):843-56. doi: 10.1002/hep.27575. Epub 2015 Jan 30.

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.

Conclusion: Etiology drives progenitor fate within diseased tissues. The liver may be a useful source of hematopoietic cells for therapy, or as therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD34 / analysis
  • CD146 Antigen / analysis
  • Cell Lineage
  • Hematopoiesis
  • Hematopoietic Stem Cells / physiology*
  • Hepacivirus / physiology*
  • Hepatitis C, Chronic / physiopathology
  • Humans
  • Liver / cytology*
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Systems Biology*
  • Viral Load

Substances

  • Antigens, CD34
  • CD146 Antigen
  • MCAM protein, human