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

Published

Journal Article

UNLABELLED: 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.

Full Text

Duke Authors

Cited Authors

  • Velazquez, VM; Uebelhoer, LS; Thapa, M; Ibegbu, CC; Courtney, C; Bosinger, SE; Magliocca, JF; Adams, AB; Kirk, AD; Knechtle, SJ; Kalman, D; Suthar, MS; Grakoui, A

Published Date

  • March 2015

Published In

Volume / Issue

  • 61 / 3

Start / End Page

  • 843 - 856

PubMed ID

  • 25331524

Pubmed Central ID

  • 25331524

Electronic International Standard Serial Number (EISSN)

  • 1527-3350

Digital Object Identifier (DOI)

  • 10.1002/hep.27575

Language

  • eng

Conference Location

  • United States