临床规模生产的人诱导多能干细胞来源的巨核细胞和血小板的成骨作用及安全性。
Osteogenic effects and safety of human induced pluripotent stem cell-derived megakaryocytes and platelets produced on a clinical scale.
作者信息
Arai Takahito, Shiga Yasuhiro, Mukai Michiaki, Takayama Naoya, Tashiro Susumu, Tajiri Ikuko, Kosaka Kentaro, Sato Masashi, Nakamura Sou, Okamoto Haruki, Kimura Seiji, Inage Kazuhide, Suzuki-Narita Miyako, Eguchi Yawara, Orita Sumihisa, Eto Koji, Ohtori Seiji
机构信息
Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, 2608670, Japan.
Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba, 2608670, Japan.
出版信息
Regen Ther. 2024 Oct 3;26:850-858. doi: 10.1016/j.reth.2024.09.012. eCollection 2024 Jun.
INTRODUCTION
Platelet-rich plasma obtained by centrifuging peripheral blood can promote osteogenesis owing to its abundant growth factors but has drawbacks, including rapid growth factor loss and inconsistent effects depending on donor factors. To overcome these issues, we were the first in the world to use freeze-dried human induced pluripotent stem cell-derived megakaryocytes and platelets (S-FD-iMPs) and found that they have osteogenesis-promoting effects. Since turbulence was found to activate platelet biogenesis and iPS cell-derived platelets can now be produced on a clinical scale by a device called VerMES, this study examined the osteogenesis-promoting effect and safety of clinical-scale FD-iMP (V-FD-iMPs) for future human clinical application.
METHOD
We administered either S-FD-iMPs, V-FD-iMPs, or saline along with artificial bone to the lumbar spine of 8-week-old male Sprague-Dawley rats (n = 4 each) and evaluated bone formation by computed tomography (CT) and pathology. Next, we administered V-FD-iMPs or saline along with artificial bone to the lumber spines of 5-week-old male New Zealand White rabbits (n = 4 each) and evaluated the bone formation by CT and pathology. Rats (n = 10) and rabbits (n = 6) that received artificial bone and V-FD-iMPs in the lumbar spine were also observed for 6 months for adverse events, including infection, tumor formation, and death.
RESULTS
Both V-FD-iMPs and S-FD-iMPs significantly enhanced osteogenesis in the lumber spines of rats in comparison with the controls 8 weeks postoperatively, with no significant differences between them. Furthermore, V-FD-iMPs vigorously promoted osteogenesis in the lumber spines of rabbits 8 weeks postoperatively. In rats and rabbits, V-FD-iMPs showed no adverse effects, including infection, tumor formation, and death, over 6 months.
CONCLUSION
These results suggest that V-FD-iMPs promote safe osteogenesis.
引言
通过离心外周血获得的富血小板血浆因其丰富的生长因子可促进骨生成，但存在缺点，包括生长因子快速流失以及因供体因素导致的效果不一致。为克服这些问题，我们在世界上首次使用冻干的人诱导多能干细胞衍生的巨核细胞和血小板（S-FD-iMPs），并发现它们具有促进骨生成的作用。由于发现湍流可激活血小板生成，且现在可通过一种名为VerMES的设备在临床规模上生产诱导多能干细胞衍生的血小板，本研究检测了临床规模的冻干诱导多能干细胞衍生的血小板（V-FD-iMPs）对未来人类临床应用的促骨生成作用和安全性。
方法
我们将S-FD-iMPs、V-FD-iMPs或生理盐水与人工骨一起给予8周龄雄性Sprague-Dawley大鼠（每组n = 4）的腰椎，并通过计算机断层扫描（CT）和病理学评估骨形成。接下来，我们将V-FD-iMPs或生理盐水与人工骨一起给予5周龄雄性新西兰白兔（每组n = 4）的腰椎，并通过CT和病理学评估骨形成。还对腰椎接受人工骨和V-FD-iMPs的大鼠（n = 10）和兔子（n = 6）观察6个月，以观察不良事件，包括感染、肿瘤形成和死亡。
结果
与对照组相比，术后8周时，V-FD-iMPs和S-FD-iMPs均显著增强了大鼠腰椎的骨生成，两者之间无显著差异。此外，术后8周时，V-FD-iMPs有力地促进了兔子腰椎的骨生成。在大鼠和兔子中，V-FD-iMPs在6个月内未显示出包括感染、肿瘤形成和死亡在内的不良反应。
结论
这些结果表明V-FD-iMPs可促进安全的骨生成。
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