Vetnuus | August 2024 13 Exploring the Tumor-Associated Risk of Mesenchymal Stem Cell Therapy in Veterinary Medicine Soyoung Jeung 1,2, Sungsoo Kim 1,2 , Jaegon Ah 1, Sanghyuk Seo 1, Umair Jan 3 , Hyejin Lee 4 and Jeong Ik Lee 3,4,* 1 VIP Animal Medical Center, 73, Dongsomun-ro, Seongbuk-gu, Seoul 02830, Republic of Korea; jeungs1007@gmail.com (S.J.); ilovekh0@vipah.co.kr (S.K.); sadgon@hanmail.net (J.A.); ssh45035@vipah.co.kr (S.S.) 2 Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea 3 Regenerative Medicine Laboratory, Center for Stem Cell Research, Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Republic of Korea; umairjan47@konkuk.ac.kr 4 Department of Veterinary Obstetrics and Theriogenology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; hyejinly@konkuk.ac.kr * Correspondence: jeongik@konkuk.ac.kr Simple Summary: This report discusses the ongoing research on, and concerns regarding, the tumor promotion associated with multipotent stem cells, with a focus on mesenchymal stem cells (MSCs) in regenerative medicine. Throughout this commentary, we explore the various impacts of MSC therapies on tumor growth that occurs in veterinary analysis. Additionally, we investigated the characteristics that rendered embryonic stem cells and induced pluripotent stem cells more tumorigenic than MSCs. Overall, despite concerns regarding tumorigenesis, limited evidence supports the increased risk of tumors associated with MSC injections. MSCs are thus considered a valuable and safe alternative in the veterinary medicine market, especially for companion animals such as dogs and cats. Moreover, bioengineered MSC-derived exosomes are preferable choices for tumor diagnosis and treatment. Abstract: Mesenchymal stem cell (MSC) therapy has been actively applied in veterinary regenerative medicine to treat various canine and feline diseases. With increasing emphasis on safe cell-based therapies, evaluations of their tumorigenic potential are in great demand. However, a direct confirmation of whether tumors originate from stem cells or host cells is not easily achievable. Additionally, previous studies evaluating injections of high doses of MSCs into nude mice did not demonstrate tumor formation. Recent research focused on optimizing MSC-based therapies for veterinary patients, such as MSC-derived extracellular vesicles in treating different diseases. This progress also signifies a broader shift towards personalized veterinary medicine, where treatments can be tailored to individual pets based on their unique genetic profiles. These findings related to different treatments using MSCs emphasize their future potential for veterinary clinical applications. In summary, because of lower tumor-associated risk of MSCs as compared to embryonic and induced pluripotent stem cells, MSCs are considered a suitable source for treating various canine and feline diseases. 1. Introduction Multipotent mesenchymal stem cells (MSCs) derived from bone marrow were first identified in 1961 [1]. Stem cells have since been actively researched for several years in both human and veterinary medicine, and commercial stem cell therapy for equine orthopedic diseases commenced in 2003 [2]. As a cornerstone of regenerative medicine, stem cell therapy has primarily been used to treat cellular damage and refractory diseases in dogs and cats [3]. However, recently, its therapeutic scope has gradually expanded, with a notable emphasis on its anti-inflammatory and immunomodulatory capabilities [4–6]. Stem cell therapy in dogs and cats utilizes either in-clinic cell production or the use of approved veterinary medical products. Japan introduced the first allogeneic adiposederived MSC-based pharmaceutical (Stemcure®, Osaka, Japan), and the UK pioneered a xenogeneic stem cell-based pharmaceutical (DogStem®, Oxfordshire, UK) using equine umbilical cord-derived MSCs, primarily for use in dogs [7,8]. Safety plays a pivotal role as a prerequisite and a fundamental element in decision making related to stem cell therapy [9]. Previous research has suggested that the side effects of stem cell therapy are minimal, generally mild, and self-limiting over a short period [10]. However, the tumor-associated risk of MSCs remains uncertain; thus, to ensure safe stem cell therapy, there is a need to assess the risk of tumorigenesis and tumor promotion. Animal model research simulates naturally occurring human diseases and is driven by the extensive parallels between animals and humans in comparative medicine [11–13]. Ongoing research has explored the tumorigenesis of MSCs after invivo injections as well as their impact on tumor growth. Moreover, some studies have demonstrated the contributions of animal models in studying human diseases, providing numerous similarities between human and companion animals [14–20]. Considering these aspects, in this commentary, our focus is on exploring the research on the tumorassociated risk of stem cell therapies in companion animals, as based on insights from human biology and medicine. The aim of this study is to thoroughly assess the safety of MSC therapy by examining it from multiple perspectives. This involves analyzing its distinct characteristics and comparing its safety profile with that of embryonic stem cells and induced pluripotent stem cells, as well as the risk associated with tumors. Additionally, this study seeks to explore how MSCs can be effectively applied in stem cell therapy. >>> 14
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