Rengasamy Mathiyazhagan, Gupta Pawan Kumar, Kolkundkar Udaykumar, Singh Gurbind, Balasubramanian Sudha, SundarRaj Swathi, Chullikana Anoop, Majumdar Anish Sen
Stempeutics Research Pvt. Ltd., Akshay Tech Park, No.72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bengaluru 560 066, India.
Indian J Med Res. 2016 Dec;144(6):852-864. doi: 10.4103/ijmr.IJMR_1842_15.
BACKGROUND & OBJECTIVES: Administration of ex vivo-expanded human bone marrow-derived mesenchymal stromal cells (hBMMSC) obtained from single donors has shown therapeutic benefits in both preclinical and clinical studies. In this study, the safety, toxicity and biodistribution profiles of a pooled hBMMSC population, produced from three healthy donors were assessed in rodent and non-rodents.
The pooled hBMMSC population was characterized by their expression of various cell surface markers, differentiation potential and immunomodulatory activity. To establish in vivo safety of the pooled cells, these were administered by various injection routes into rodents and non-rodents to determine overall toxicity, biodistribution and tumorigenic potential in a series of preclinical studies.
Single injections of hBMMSC at various doses through intravenous or intramuscular routes did not cause toxicity in rats and rabbits. In addition, repeat administration of hBMMSC was also well tolerated by rats, and no prenatal toxicity was observed by multiple administration in the same animal species. Ex vivo-expanded and cryopreserved hBMMSCs did not induce tumour formation in severe combined immunodeficient (SCID) mice.
INTERPRETATION & CONCLUSIONS: Our results showed that the pooled hBMMSC population was non-toxic, non-teratogenic and non-tumorigenic in animals. Further studies need to be done to find out if it can be safely administered in human patients.
在临床前和临床研究中，给予从单一供体获取的体外扩增人骨髓间充质基质细胞（hBMMSC）已显示出治疗益处。在本研究中，对由三名健康供体产生的混合hBMMSC群体在啮齿动物和非啮齿动物中的安全性、毒性和生物分布情况进行了评估。
通过混合hBMMSC群体表达的各种细胞表面标志物、分化潜能和免疫调节活性对其进行表征。为确定混合细胞在体内的安全性，在一系列临床前研究中，通过多种注射途径将这些细胞给予啮齿动物和非啮齿动物，以确定总体毒性、生物分布和致瘤潜力。
通过静脉或肌肉途径以不同剂量单次注射hBMMSC对大鼠和兔子均未造成毒性。此外，大鼠对hBMMSC的重复给药也具有良好的耐受性，在同一动物物种中多次给药未观察到产前毒性。体外扩增并冷冻保存的hBMMSC在严重联合免疫缺陷（SCID）小鼠中未诱导肿瘤形成。
我们的结果表明，混合hBMMSC群体在动物中无毒、无致畸性且无致瘤性。需要进一步研究以确定其是否可安全用于人类患者。
