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Functional Evaluation of Mesenchymal Stem Cells Derived from Canine Induced Pluripotent Stem Cells

ABSTRACT: Comparison of gene expression profiles of canine induced pluripotent stem cells (iPSC) and iPS derived mesenchymal stem cells (iMSC) by microarray Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from adipose or bone marrow tissues from younger donors, in part due to ease of procurement and to the superior immune modulatory activity of young MSC. However, use of MSC from multiple unrelated donors makes it difficult to standardize MSC cellular products with uniform immune modulatory properties. One solution to this problem is the use of MSC derived from induced pluripotent stem cells (iPSC), as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including their immune modulatory properties and their potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype even after multiple passages, did not form teratomas when inoculated in immune deficient mice, and did not induce tumor formation in purpose-bred dogs following systemic injection. The immune potency of iMSC was similar to that of adipose and bone-marrow derived MSC with respect to suppression of T cell and DC activation. We concluded therefore that iMSC were phenotypically stable, immunologically potent, and safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE94081 | GEO | 2017/01/26

SECONDARY ACCESSION(S): PRJNA368749

REPOSITORIES: GEO

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Project description:Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, andpremature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC(iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

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Functional Evaluation of Mesenchymal Stem Cells Derived from Canine Induced Pluripotent Stem Cells

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