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Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage.

ABSTRACT: Human adipose-derived stromal/stem cells (ASCs) display potential to be used in regenerative stem cell therapies and as treatments for inflammatory and autoimmune disorders. Despite promising use of ASCs as therapeutics, little is known about their susceptibility to infectious agents. In this study, we demonstrate that ASCs are highly susceptible to human cytomegalovirus (HCMV) infection and permissive for replication leading to release of infectious virions. Additionally, many basic ASC functions are inhibited during HCMV infection, such as differentiation and immunomodulatory potential. To our knowledge this is the first study examining potential adverse effects of HCMV infection on ASC biology. Our results suggest, that an active HCMV infection during ASC therapy may result in a poor clinical outcome due to interference by the virus.

SUBMITTER: Zwezdaryk KJ

PROVIDER: S-EPMC4836472 | biostudies-literature | 2016 Jan-Mar

REPOSITORIES: biostudies-literature

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Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage.

Zwezdaryk K J KJ Ferris M B MB Strong A L AL Morris C A CA Bunnell B A BA Dhurandhar N V NV Gimble J M JM Sullivan D E DE

Adipocyte 20151209 1

Human adipose-derived stromal/stem cells (ASCs) display potential to be used in regenerative stem cell therapies and as treatments for inflammatory and autoimmune disorders. Despite promising use of ASCs as therapeutics, little is known about their susceptibility to infectious agents. In this study, we demonstrate that ASCs are highly susceptible to human cytomegalovirus (HCMV) infection and permissive for replication leading to release of infectious virions. Additionally, many basic ASC functio ...[more]

PMID: 27144097

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Project description:BackgroundAdipose-derived stem cells (ASC) and adipocytes are involved in numerous physiological and pathophysiological conditions, which have been extensively described in subcutaneous and visceral fat depots over the past two decades. However, much less is known about ASC and adipocytes outside classical fat tissue depots and their necessity in tissue remodeling after injury. Therefore, we investigated the etiology of adipocytes in human granulation tissue and define their possible role wound healing.MethodsIdentification of human wound tissue adipocytes was determined by immunohistochemical staining of granulation tissue sections from patients undergoing surgical debridement. Stromal cell fractions from granulation tissue and subcutaneous fat tissue were generated by collagenase type II-based protocols. Pro- and anti-inflammatory wound bed conditions were mimicked by THP1- and CD14+ monocyte-derived macrophage models in vitro. Effects of macrophage secretome on ASC differentiation and metabolism were determined by immunoblotting, flow cytometry, and microscopy assessing early and late adipocyte differentiation states. Functional rescuing experiments were conducted by lentiviral transduction of wildtype PPARG, IL1RA, and N-chlorotaurine (NCT) treatment.ResultsSingle and clustered adipocyte populations were detected in 11 out of 13 granulation tissue specimens and single-cell suspensions from granulation tissue showed adipogenic differentiation potential. Pro-inflammatory signaling by IFNG/LPS-stimulated macrophages (M (IFNG/LPS)) inhibited the maturation of lipid droplets in differentiated ASC. In contrast, anti-inflammatory IL4/IL13-activated macrophages (M (IL4/IL13)) revealed minor effects on adipocyte development. The M (IFNG/LPS)-induced phenotype was associated with a switch from endogenous fatty acid synthesis to glycolysis-dominated cell metabolism and increased pro-inflammatory cytokine production. Impaired adipogenesis was associated with increased, but seemingly non-functional, CEBPB levels, which failed to induce downstream PPARG and CEBPA. Neither transgenic PPARG overexpression, nor inhibition of IL1B was sufficient to rescue the anti-adipogenic effects induced by IFNG/LPS-activated macrophages. Instead, macrophage co-treatment during stimulation with NCT, a mild oxidant produced by activated granulocytes present in human wounds in vivo, significantly attenuated the anti-adipogenic effects.ConclusionsIn conclusion, the appearance of adipocytes in wound tissue indicates a prevailing anti-inflammatory environment that could be promoted by NCT treatment and may be associated with improved healing outcomes.

Dataset Information

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage.

Publications

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage.

Similar Datasets

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