This study evaluated the adverse effects of MSC transplantation by IV infusion of allogenic MSCs in dogs and examined the long-term risk of tumorigenesis based on physical examination, blood tests, and radiographs. Apart from the 3 cases, among the 314 cases (40 dogs) that showed mild vasculitis, no other significant adverse effects of MSC therapy were detected within 6 months of the first MSC treatment. The risk of tumorigenesis due to MSC therapy, which was evaluated by conducting long-term monitoring of neoplasms, detected no new neoplasms within the 6-month follow-up period.
Numerous studies have assessed the safety of intravenously administered MSCs. In a study involving human patients with chronic inflammation, treatment with human umbilical cord blood-derived MSCs (hUBC-MSCs) was reported to be safe and efficient (Mehling et al. 2015). Another study that performed intravenous administration of allogeneic AT-MSCs in cats with chronic kidney disease reported no significant adverse effects (Quimby et al. 2013, 2016). In two other studies performed on dogs with inflammatory bowel disease and refractory atopic dermatitis, IV infusion of allogenic canine AT-MSCs showed no systemic adverse effects during the follow-up period of six weeks and six months, respectively (Pérez-Merino et al. 2015; Villatoro et al. 2018).
However, there are many conflicting reports on the tumorigenic potential of MSCs. Murine bone marrow-derived MSCs undergo malignant transformations in vitro and in vivo (Jeong et al. 2011; Toar et al. 2007). In contrast, another study reported that human MSCs are not susceptible to malignant transformation in long-term in vitro cultures (Bernardo et al. 2007). Furthermore, various studies have reported that the administration of hUCB-MSCs in immunodeficient mice does not result in tumor formation, suggesting that hUCB-MSCs lack tumorigenicity in vivo (Park et al. 2016; Wang et al. 2013). However, studies have rarely monitored the long-term risk of tumorigenesis of allogeneic MSC infusion in dogs, and our study suggests that allogeneic canine AT-MSCs do not have tumorigenic potential.
This study has a few limitations. First, the sample size used in this study was small, as only a limited number of dogs satisfied the inclusion criteria. Second, the follow-up period was capped at six months, longer monitoring period is necessary to assess the long-term safety aspects of MSC therapy. Despite these limitations, observations from this study are important because it is the first study to assess the long-term safety of IV infusion of allogenic AT-MSCs in client-owned dogs.
Intravenous administration of allogenic AT-MSCs in client-owned dogs treated for various diseases did not show any adverse effects, as observed by physical examination, blood tests, and radiography, in a majority of the cases. Furthermore, new neoplasms were not observed during the period of at least six months following MSC transplantation, suggesting a minimal risk of tumorigenesis associated with MSC therapy. Thus, allogenic MSC infusion is a useful and a relatively safe therapeutic approach for dogs.