Vetnuus | August 2024 15 5. Why Do Embryonic Stem Cells (ESCs) and Induced Pluripotent Stem Cells (iPSCs) have a Higher Oncogenic Risk Than MSCs? Multipotent MSCs, being distinct from pluripotent stem cells such as ESCs and iPSCs, exhibit a more limited differentiation capacity [50]. These stem cells can differentiate into chondrogenic, adipogenic, and osteogenic lineages and maintain a high ability for selfrenewal [51]. Controlled differentiation with multipotency is a crucial aspect for therapeutic applications, as it provides researchers and clinicians a means to guide the cells towards desired lineages. In controlled differentiation, the MSCs are directly differentiated into specific cell types under controlled conditions. This characteristic makes multipotent stem cells a promising tool for regenerative therapies in veterinary medicine [52]. In contrast, pluripotent stem cells can differentiate into all three germ layers as well as all types of cells exhibiting unlimited proliferation [53]. Similarly, no major health concerns were reported in small-sized animals for clinical trials conducted using MSCs in regenerative medicine fields, which means that MSC treatments are relatively safer than pluripotent stem cell treatments since they have a higher rate of proliferation [30]. These undifferentiated pluripotent stem cells can contribute to tumor formation, both benign and malignant, in immunodeficient animal models via continued proliferation after an in vivo transplantation. The reprogramming methods for iPSCs are broadly classified into viral and nonviral methods [54]. The initial iPSCs were induced from adult-derived cells through retroviral transfection, incorporating four reprogramming factors: Oct3/4, Sox2, Klf4, and cMyc. These factors reprogram somatic cells into cells with ESC-like conditions [55]. These are also the main pluripotency factors in ESCs [56] and are closely associated with tumorigenesis. Pluripotency factors such as Sox2 and Klf-4 in ESCs and iPSCs promote tumorigenesis [57,58]. Sox2 can ensure tumor cell survival and is oncogenic in several kinds of cancers of the lung and esophagus, such as carcinomas [59]. In the context of MSC therapies, it has been documented that the reactivation of the c-myc oncogene can contribute to tumor formation. Similarly, the factor Klf-4, which promotes cellular proliferation in breast cancer by suppressing P53, a tumor suppressor, also plays a role in suppression. Therefore, these pluripotency-related transcription factors, including c-myc, can potentially induce oncogenesis and malignancies, emphasizing the necessity of comprehensive safety assessments in MSC-based therapies [58–60]. Furthermore, pluripotent stem cells can undergo genetic alterations— chromosome abnormalities, variations in copy number, and single nucleotide mutations—during in vitro experimentations [61]. Although the likelihood of a single genetic mutation causing tumorigenesis is low, an accumulation of mutations in tumor-related genes increases the risk of tumorigenesis [62]. Thus, concerns regarding the tumorigenesis of ESCs and iPSCs persist and represent a critical hurdle to patient treatment. 6. Conclusions Tumorigenesis is a complex interplay between cellular genetic factors and environmental influences, with its precise etiology and mechanisms yet to be fully elucidated. Given the proliferative characteristics of stem cells, concerns regarding the tumor-associated risk of MSCs remain unresolved. This report aimed to address the increasing demand for safety Animals 2024, 14, 994 5 of 7 in the expanding market of MSC therapy and to bridge the gap in our understanding of tumor promotion of stem cells. We probed the capacity of MSCs to induce tumor formation in vivo. The prevailing consensus suggests that robust evidence supporting an increased tumor incidence associated with MSC injections is limited. Moreover, the process of distinguishing the region of tumor origin remains ambiguous. Therefore, it may be preemptive to conclude that MSC injections cause risks related to tumors, as the relationship between MSCs and tumorigenesis or tumor promotion remains unrevealed in many cases. The dual nature of MSCs presents both challenges and opportunities in the realm of veterinary oncology. Exploring the potential of tumor promotion as well as the tumorigeneses of MSC therapy requires an understanding of the interplay between both pro-tumorigenic and anti-tumorigenic effects. Veterinary researchers and clinicians can exploit this dual nature to develop targeted and personalized approaches for cancer treatments in companion animals, thereby facilitating innovative veterinary medicine strategies. Concurrently, the use of MSC-derived exosomes in veterinary medicine presents a promising venue for therapeutic interventions, potentially aiding in early cancer detection and treatment. Although MSCs may have limited multipotency compared to ESCs and iPSCs, they offer the distinct advantage of a lower risk of tumor promotion. MSCs can thus be considered a valuable and safe choice for future treatments of canine and feline patients. In this commentary, we explored the tumor-associated risk of MSC therapies in veterinary medicine. The prospects of MSC therapies require a comprehensive understanding of tumor promotion, the development of safer treatment modalities, and exploration of novel applications in both human and veterinary medicine. Continued research efforts will remain vital to unlocking the full potential of MSCbased therapies while ensuring their safety and efficacy in clinical applications. v Author Contributions: Conceptualization: S.J., S.K., J.A., S.S., U.J., H.L. and J.I.L.; Investigation: S.J., S.K., J.A., S.S., U.J. and H.L.;Writing—original draft preparation: S.J., S.K., J.A., S.S., U.J., H.L. and J.I.L.; Writing—review and editing: S.J., S.K., J.A., S.S., U.J., H.L. and J.I.L.; Supervision: J.I.L. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by a National Research Foundation of Korea (NRF) grant fundedby the Korean government (MIST) (No. 2022R1F1A1068732). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare that they have no competing interests. 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