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Study on therapeutic effects of porcine induced pluripotent stem cells in preclinical models of osteoporosis
induced pluripotent stem cells
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|摘要:||骨質疏鬆症（osteoporosis）發生原因為破骨細胞（osteclasts）與成骨細胞（osteblasts）活性的動態平衡失衡所致，以致骨質重吸收（bone resoprtion）遠大於骨質形成（bone formation），最終導致骨質流失（bone loss）。目前已有利用藥物或細胞移植治療的方式，來改善骨質流失。誘導多能性幹細胞（induced pluripotent stem cells, iPSCs）之特性與胚幹細胞（embryonic stem cells, ESCs）相似，於特定環境下可分化為各種組織。本試驗即利用豬耳朵纖維母細胞建立豬誘導多能性幹細胞（porcine iPSCs, piPSCs），以人類hOct4、hSox2、hKlf4與hc-Myc基因以慢病毒載體（lentivirus vector）轉染入表現綠色螢光蛋白質的豬耳朵纖維母細胞內。結果顯示，轉染後的細胞擁有體外形成類胚體（embryoid body, EB）與分化為三胚層（three germ layers），以及體內分化為畸胎瘤（teratomas）等胚幹細胞特性。此細胞稱為表現綠色螢光蛋白質之豬誘導多能性幹細胞（green fluorescent protein expressing porcine induced pluripotent stem cells, piPSCs/GFP+）。接著，再將其誘導分化為成骨細胞，探討其治療骨質疏鬆症大鼠與蘭嶼豬（Lanyu pigs）之效果。piPSCs/GFP+經骨生成培養液培養4週後，細胞有鈣鹽沉積現象，並表現骨連接素（osteonectin）、骨鈣素（osteocalcin）與膠原蛋白I型（collagen type I）等成骨細胞特異性蛋白質。此分化之細胞稱為豬誘導多能性幹細胞衍生之成骨細胞（piPSCs/GFP+-derived osteoblast-like cells）。大鼠經卵巢移除、鈣含量0.1%之飼糧餵飼與3 mg/kg的prednisolone處理3個月後，股骨（femurs）有較低的骨小樑體積百分比（percent bone volume）、骨表面積/體積比（bone surface/volume ratio）、骨小樑厚度（trabecular thickness）與骨小樑數目（trabecular number），而有較高的骨小樑分離度（trabecular separation）與總孔隙率（total porosity）。將豬誘導多能性幹細胞衍生之成骨細胞移植於股骨骨髓腔3個月後，可修復骨小樑缺陷，且移植處有骨質新生現象。蘭嶼豬經卵巢移除、鈣含量0.5%之飼糧餵飼與1 mg/kg的prednisolone處理12個月後，其脛骨（tibiae）骨小樑體積百分比、骨表面積/體積比、骨小樑厚度、骨小樑數目，以及總孔隙率等指標，皆與控制組有顯著差異。將豬誘導多能性幹細胞衍生之成骨細胞移植於脛骨骨髓腔6個月後，於細胞移植處同樣可修復骨小樑缺陷，且有骨質再生現象。研就結果顯示，豬誘導多能性幹細胞衍生之成骨細胞可改善骨質流失現象。這些結果可強化piPSCs於再生醫學上之應用。|
The main cause of osteoporosis is due to the imbalance of osteoclast and osteoblast activity, and bone resoprtion surpasses bone formation. This phenomenon results in bone loss. Nowadays, drug treatments and cell therapy have been used to ameliorate bone loss. The properties of induced pluripotent stem cells (iPSCs) are similar to those of embryonic stem cells (ESCs), and the cells can differentiate into different types of cells under certain culture conditions. In the present study, we established porcine iPSCs (piPSCs) from porcine ear fibroblasts and investigated the therapeutic effects of piPSCs on rat and Lanyu pig model of osteoporosis. The green fluorescent protein expressing ear fibroblasts were infected with human hOct4, hSox2, hKlf4, and hc-Myc cloned into lentivirus vectors. After transfection, the infected cells expressed the properties of ESCs, such as in vitro embryoid body formation, in vitro three germ layer differentiation, and in vivo teratoma formation. The established cells were named as green fluorescent protein expressing porcine induced pluripotent stem cells (piPSCs/GFP+). After culturing in osteogenic medium for four weeks, piPSCs/GFP+ showed calcium deposition and expressed specific protein markers of osteoblasts, such as osteonectin, osteocalcin, and collagen type I. The differentiated cells were named as piPSCs/GFP+-derived osteoblast-like cells. After three months of ovariectomy, 0.1% calcium diet feeding, and 3 mg/kg of prednisolone treatment, the rat femurs exhibited low level of percent bone volume, bone surface/volume ratio, trabecular thickness, and trabecular number but showed high level of trabecular separation and total porosity. After transplanting piPSCs/GFP+-derived osteoblast-like cells into the medullary cavity of the femurs for three months, the trabecular bone defects were restored to the level as the control group, and trabecular bone regeneration was evident at the transplanted sites. Furthermore, after twelve months of ovariectomy, 0.5% calcium diet feeding, and 1 mg/kg of prednisolone treatment, the level of percent bone volume, bone surface/volume ratio, trabecular thickness, trabecular number, and total porosity in the tibiae of Lanyu pigs were significantly different from the control group. After transplanting piPSCs/GFP+-derived osteoblast-like cells into the medullary cavity of the tibiae for six months, the trabecular bone defects at the transplanted sites were also recovered to the level as the control group, and bone regeneration was evident at the transplanted site. These results revealed that piPSCs/GFP+-derived osteoblast-like cells can ameliorate bone loss, and the results can enhance the application of piPSCs on regenerative medicine.
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