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Two Methods of Heterokaryon Formation to Discover HCV Restriction Factors
Published on: July 16, 2012
Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development
Victoria M Velazquez1, Luke S Uebelhoer, Manoj Thapa
1Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA.
Insights
Chronic liver disease impacts liver stem cells, with Hepatitis C virus altering hematopoietic progenitor cells. These cells show enhanced growth, suggesting potential therapeutic applications or targets.
Area of Science:
- Hepatology
- Immunology
- Stem Cell Biology
Background:
- Chronic liver disease is linked to myeloid dendritic cell accumulation.
- Liver-resident CD34+ cells, including stem and progenitor cells, are crucial for liver health.
- Understanding disease effects on these cells is vital for therapeutic strategies.
Purpose of the Study:
- To investigate the role of liver disease etiology on myelopoiesis and CD34+ cell subsets.
- To characterize the distinct properties of CD34+CD146+ and CD34+CD146- cells in different liver diseases.
- To assess the hematopoietic potential of liver-derived CD34+CD146- cells in alcohol liver disease (ALD), nonalcoholic steatohepatitis (NASH), and chronic hepatitis C virus (HCV) infection.
Main Methods:
- Systems biology approach utilizing gene expression profiling and computational modeling.
- Analysis of liver CD34+ cell subsets (CD34+CD146+ and CD34+CD146-) in patients with end-stage liver disease.
- Comparative analysis of CD34+ cell subsets in ALD, NASH, and HCV cohorts.
- In vitro culture assays to assess hematopoietic function and progenitor cell growth.
Main Results:
- Liver CD34+ cell frequencies were reduced in NASH and HCV compared to ALD, correlating with viral load in HCV.
- CD34+CD146+ cells showed increased expression of endothelial cell genes with minimal disease impact.
- CD34+CD146- cells from HCV patients exhibited a distinct gene expression signature related to cell cycle, DNA repair, and immune cell development.
- HCV CD34+CD146- cells demonstrated superior hematopoietic growth and differentiation potential compared to ALD and NASH counterparts.
- Disease-specific phenotypic alterations were observed in myeloid progeny cells.
Conclusions:
- Liver disease etiology significantly influences progenitor cell fate within the liver.
- Liver-derived hematopoietic progenitor cells, particularly from HCV patients, show enhanced function.
- The liver may serve as a source for hematopoietic cells in cell-based therapies or as targets for therapeutic intervention.
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.
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