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Effects of Freeze-Thawing and Intravenous Infusion on Mesenchymal Stromal Cell Gene Expression

ABSTRACT: Mesenchymal stromal cells (MSC) are increasingly used as an investigative therapeutic product for immune disorders and degenerative disease. Typically, MSC are isolated from human tissue, expanded in culture and cryopreserved until usage. The safety and efficacy of MSC therapy will depend on the phenotypical and functional characteristics of MSC. The freeze-thawing procedure may change these characteristics. Furthermore, the microenvironment that the cells encounter after administration may impact the properties of MSC. It has been demonstrated that the large majority of MSC localize to the lungs after intravenous infusion, making this the site to study the effects of the in vivo milieu on administered MSC. In the present study we investigated the effect of freeze-thawing and of the mouse lung microenvironment on human adipose tissue-derived MSC. The effect of freeze-thawing on the whole genome expression profile of MSC was small and did not exceed inter-donor differences. There were no major changes in the expression of hemostatic regulators on transcriptional level, but significantly increased expression of procoagulant tissue factor on the surface of thawed adipose MSC, correlating with increased procoagulant activity of thawed cells after blood exposure in vitro and after infusion to mice. Exposure for 2h to the lung microenvironment had a major effect on MSC gene expression and affected several immunological and metabolic pathways. This indicates that MSC undergo functional changes shortly after infusion and this may influence the efficacy of MSC to modulate inflammatory responses. The results of this study demonstrate that MSC rapidly alter in response to the local milieu and that disease specific conditions may shape MSC after administration.

OTHER RELATED OMICS DATASETS IN: PRJNA306176

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE76081 | GEO | 2016/02/01

SECONDARY ACCESSION(S): PRJNA306176

REPOSITORIES: GEO

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Project description:Background: Systemic sclerosis (SSc) is a chronic autoimmune disease. We tested the safety of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSC) to treat severe SSc. Methods: We conducted the first prospective, monocentric, dose-escalation, phase I/II clinical trial investigating the feasibility and safety of a single allogeneic BM-MSC infusion in 20 severe SSc patients who were refractory or had a contraindication to conventional immunosuppressive therapy or autologous hematopoietic stem cell transplant. Patients were assigned to an infusion of either 1x10^6 BM-MSC/kg or 3x10^6 BM-MSC/kg obtained from 20 independent intrafamilial donors. Primary endpoint was the rate of grade ≥ 3 Severe Adverse Events (SAE; NCI Common Terminology Criteria for Adverse Events (v5.0)) in the first 10 days post-BM-MSC infusion. Secondary endpoints included adequacy of BM-MSC production, medium-term SAE, as well as clinical and immunological response. Findings: No Grade 3 ≥ SAE occurred in the first 10 days following MSC infusion in the 20 SSc patients. A significant improvement in modified Rodnan Skin Score (p<0.0001) was observed after BM-MSC infusion, which peaked at 3 months and was sustained for 1 year. No changes in health-related quality of life or pulmonary function were observed. CD8pos T-Cell and NK cell counts slightly increased after infusion (p<0.05) and two patients developed de novo donor-specific anti-HLA. Circulating TGF-β level at baseline was significantly higher in non-responder compared to responder patients (p<0.05). A pattern of low IDO activity, CCL2 production, and HLA-DR expression in BM-MSC batches under in vitro stimulation by IFN-beta was associated with a lack of clinical response in recipient SSc patients. Interpretation: A single infusion of allogeneic BM-MSC transplant was safe in severe SSc patients and triggered short-term disease modifying effects. Clinical response was associated with both the recipients biological features and the functional properties of infused BM-MSC.

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Effects of Freeze-Thawing and Intravenous Infusion on Mesenchymal Stromal Cell Gene Expression

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