All Angelo H, Gharibani Payam, Gupta Siddharth, Bazley Faith A, Pashai Nikta, Chou Bin-Kuan, Shah Sandeep, Resar Linda M, Cheng Linzhao, Gearhart John D, Kerr Candace L
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Singapore Institute for Neurotechnology, National University of Singapore, Singapore, Singapore; Departments of Orthopedic Surgery, Biomedical Engineering and Medicine, Division of Neurology, National University of Singapore, Singapore, Singapore.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2015 Jan 30;10(1):e0116933. doi: 10.1371/journal.pone.0116933. eCollection 2015.
Induced pluripotent stem (iPS) cells are at the forefront of research in regenerative medicine and are envisaged as a source for personalized tissue repair and cell replacement therapy. Here, we demonstrate for the first time that oligodendrocyte progenitors (OPs) can be derived from iPS cells generated using either an episomal, non-integrating plasmid approach or standard integrating retroviruses that survive and differentiate into mature oligodendrocytes after early transplantation into the injured spinal cord. The efficiency of OP differentiation in all 3 lines tested ranged from 40% to 60% of total cells, comparable to those derived from human embryonic stem cells. iPS cell lines derived using episomal vectors or retroviruses generated a similar number of early neural progenitors and glial progenitors while the episomal plasmid-derived iPS line generated more OPs expressing late markers O1 and RIP. Moreover, we discovered that iPS-derived OPs (iPS-OPs) engrafted 24 hours following a moderate contusive spinal cord injury (SCI) in rats survived for approximately two months and that more than 70% of the transplanted cells differentiated into mature oligodendrocytes that expressed myelin associated proteins. Transplanted OPs resulted in a significant increase in the number of myelinated axons in animals that received a transplantation 24 h after injury. In addition, nearly a 5-fold reduction in cavity size and reduced glial scarring was seen in iPS-treated groups compared to the control group, which was injected with heat-killed iPS-OPs. Although further investigation is needed to understand the mechanisms involved, these results provide evidence that patient-specific, iPS-derived OPs can survive for three months and improve behavioral assessment (BBB) after acute transplantation into SCI. This is significant as determining the time in which stem cells are injected after SCI may influence their survival and differentiation capacity.
诱导多能干细胞（iPS细胞）处于再生医学研究的前沿，被设想为个性化组织修复和细胞替代疗法的来源。在此，我们首次证明，少突胶质前体细胞（OPs）可源自使用游离型、非整合质粒方法或标准整合逆转录病毒生成的iPS细胞，这些细胞在早期移植到受损脊髓后能够存活并分化为成熟的少突胶质细胞。在所有测试的3个细胞系中，OP分化效率占总细胞数的40%至60%，与源自人类胚胎干细胞的细胞系相当。使用游离型载体或逆转录病毒生成的iPS细胞系产生的早期神经前体细胞和神经胶质前体细胞数量相似，而源自游离型质粒的iPS细胞系产生更多表达晚期标志物O1和RIP的OPs。此外，我们发现，大鼠中度挫伤性脊髓损伤（SCI）后24小时移植的iPS衍生OPs（iPS-OPs）存活约两个月，超过70%的移植细胞分化为表达髓鞘相关蛋白的成熟少突胶质细胞。移植OPs使损伤后24小时接受移植的动物中有髓轴突数量显著增加。此外，与注射热灭活iPS-OPs的对照组相比，iPS治疗组的空洞大小减少了近5倍，胶质瘢痕形成减少。尽管需要进一步研究以了解其中涉及的机制，但这些结果提供了证据，表明患者特异性的、iPS衍生的OPs在急性移植到SCI后能够存活三个月并改善行为评估（BBB）。这一点很重要，因为确定SCI后注射干细胞的时间可能会影响它们的存活和分化能力。
