Human Adipose-Derived Stem Cells Ameliorate Cigarette Smoke-Induced Murine Myelosuppression via Secretion of TSG-6

Abstract

Objective Bone marrow-derived hematopoietic stem and progenitor cells (HSC/HPC) are critical to homeostasis and tissue repair. The aims of this study were to delineate the myelotoxicity of cigarette smoking (CS) in a murine model, to explore human adipose-derived stem cells (hASC) as a novel approach to mitigate this toxicity, and to identify key mediating factors for ASC activities. Methods C57BL/6 mice were exposed to CS with or without i.v. injection of regular or siRNA-transfected hASC. For in vitro experiments, cigarette smoke extract (CSE) was used to mimic the toxicity of CS exposure. Analysis of bone marrow hematopoietic progenitor cells (HPC) were performed both by flow cytometry and colony forming unit assays. Results In this study, we demonstrate that as few as three days of CS exposure result in marked cycling arrest and diminished clonogenic capacity of HPC, followed by depletion of phenotypically-defined HSC/HPC. Intravenous injection of hASC substantially ameliorated both acute and chronic CS-induced myelosuppression. This effect was specifically dependent on the anti-inflammatory factor TSG-6, which is induced from xenografted hASC, primarily located in the lung and capable of responding to host inflammatory signals. Gene expression analysis within bone marrow HSC/HPC revealed several specific signaling molecules altered by CS and normalized by hASC. Conclusion Our results suggest that systemic administration of hASC or TSG-6 may be novel approaches to reverse cigarette smoking-induced myelosuppression.

Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury

“…In support of prior studies, our analysis of multiple section of the kidneys has clearly shown minimal, if any, homing and retention of Celltracker-CMTPXlabelled hASCs in the treated kidneys. This supports the hypothesis that therapeutic effects of ASC are mediated by paracrine activity at a distance [54]. Further studies will be conducted to specifically assess the reno-and vascular protective effects of concentrated media conditioned by ASC.…”

TNF-stimulated gene 6 promotes formation of hyaluronan–inter-α-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness

“…It should be noted that TSG-6 has been shown to have prominent anti-inflammatory activity in a range of diseases and environmental exposures, including lung inflammation after endotoxin (21) and bleomycin exposures (22). In fact, TSG-6 has been postulated to be the crucial factor determining beneficial effects of therapeutically applied stem cells in diverse conditions, such as myocardial infarction (25), peritonitis (24), or myelosuppression (44). We believe that the apparent discrepancy between these reports and our study, as well as other studies supporting an adverse role for TSG-6 in chronic allergic lung inflammation (3), is due to the inflammatory context, in particular the dominant mechanism behind the observed phenotype.…”

Peripheral Nerve Repair: Multimodal Comparison of the Long-Term Regenerative Potential of Adipose Tissue-Derived Cells in a Biodegradable Conduit

“…Xie et al found that anti-inflammatory proteins, which are induced from xenografted hASCs, are capable of responding to host inflammatory signals [42]. In a former study of our group, it was decided to perform xenogeneic transplantation experiments as a model of maximal HLA mismatch since no allogeneic model is available for human cells due to ethical reasons [43].…”