Abstract
BackgroundAdipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular, and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs, with an emphasis on their immunomodulatory capacity and transcriptome.MethodsHuman and feline ASCs were evaluated for phenotype, immunomodulatory profile, and transcriptome. Additionally, transwells were used to determine the role of cell-cell contact in ASC-mediated inhibition of lymphocyte proliferation in both humans and cats.ResultsSimilar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity, and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen-activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern, including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta, and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of three unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis; 2) cell adhesion; 3) response to oxidative stress; and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs.ConclusionsFindings suggest that feline ASCs modulate lymphocyte proliferation using soluble mediators that mirror the human ASC secretion pattern. Uninduced feline ASCs have similar gene expression profiles to uninduced human ASCs, as revealed by transcriptome analysis. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.
Highlights
Adipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases
The surface protein expression on feline and human ASCs was compared using markers that define Mesenchymal stem cell (MSC) [1]. Both feline and human ASCs were strongly positive for CD44, CD90, and CD105, and were negative for leukocyte markers (CD18 and CD45), and MHCII (Fig. 1e and f) [31, 52, 53]
Others have established the full trilineage differentiation capacity of feline ASCs, including chondrogenic and adipogenic differentiation [52, 54,55,56,57]. These data suggest that feline ASCs are karyotypically normal, meet the minimal criteria of multipotent stem cells and are smaller but otherwise morphologically and phenotypically identical to human ASCs
Summary
Adipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. ASCs appear to be highly enriched in immune-related genes and may have advantages in terms of proliferation, stability, and immunomodulatory ability, perhaps as a result of their retaining the metabolic and inflammatory modulating transcriptome native to its tissue [3,4,5,6,7]. The increased recognition of the role of MSCs in immunomodulation, combined with successes in phase I–III clinical trials in humans using stem cell therapy for inflammatory and immune-mediated diseases, has resulted in recommendations that immune functional assays be developed as potency-release criteria for advanced-phase clinical trials [18]
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