TAKAHIRO TESHIMA

Introduction The therapeutic efficacy of mesenchymal stromal cells (MSCs) in inflammatory bowel disease is not completely known and is not consistent. Priming with inflammatory cytokines has been proposed to adapt MSCs to an inflammatory environment to have them ready to counteract it, but may have undesirable effects on MSCs, such as increased immunogenicity. In this study, we hypothesized that priming MSCs with inflamed intestinal tissue would more effectively enhance their therapeutic effect on intestinal inflammation. Methods The capacity of canine adipose-derived MSCs (cADSCs) primed with colon tissue homogenates from mice with experimentally induced colitis or a combination of tumor necrosis factor-α and interferon-γ to inhibit T-cell proliferation was analyzed, along with their own apoptosis, proliferation, cell surface marker expression, and transcriptome. In addition, colitis mice were treated with the primed cADSCs to assess colitis severity and immune cell profile. Results Priming with cytokines induced apoptosis, decreased cell proliferation, and major histocompatibility complex-II gene expression in cADSCs, but these adverse effects were mild or absent with colitis-tissue priming. cADSCs primed with colitis tissue reduced the severity of colitis via the induction of M2 macrophages and T-regulatory cells and suppression of T-helper (Th)1/Th17-cell responses, and their effects were comparable to those of cytokine-primed cells. Discussion Our results emphasize the importance of the activation of MSCs by the appropriate microenvironment to maximize their therapeutic effect.

Inflammatory bowel disease (IBD) is a major subtype of chronic enteropathies in dogs and cats. Conventional drugs such as immunomodulatory medicines as glucocorticoids and/or other anti-inflammatory are mainly applied for treatment. However, these drugs are not always effective to maintain remission from IBD and are limited by unacceptable side effects. Hence, more effective and safe therapeutic options need to be developed. Mesenchymal stem cells (MSCs) are multipotent stem cells with a self-renewal capacity, and have immunomodulatory, anti-inflammatory, anti-fibrotic, and tissue repair properties. Therefore, the application of MSCs as an alternative therapy for IBD has great potential in veterinary medicine. The efficacy of adipose tissue-derived MSC (ADSC) therapy for IBD in dogs and cats has been reported, including numerous studies in animal models. However, treatment outcomes in clinical trials of human IBD patients have not been consistent with preclinical studies. MSC-based therapy for various diseases has received widespread attention, but various problems in such therapy remain, among which no consensus has been reached on the preparation and treatment procedures for MSCs, and cellular heterogeneity of MSCs may be an issue. This review describes the current status of ADSC therapy for canine and feline IBD and summarizes the cellular heterogeneity of canine ADSCs, to highlight the necessity for further reduction or elimination of MSCs heterogeneity and standardization of MSC-based therapies.