Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
YiPSCELL Inc., 47-3, Banpo-dearo 39-gil, Seocho-gu, Seoul, Republic of Korea.
Stem Cell Res Ther. 2022 Jul 15;13(1):303. doi: 10.1186/s13287-022-02987-w.
The rarity of systemic sclerosis (SSc) has hampered the development of therapies for this intractable autoimmune disease. Induced pluripotent stem cell (iPSC) can be differentiated into the key disease-affected cells in vitro. The generation of patient-derived iPSCs has opened up possibilities for rare disease modeling. Since these cells can recapitulate the disease phenotypes of the cell in question, they are useful high-throughput platforms for screening for drugs that can reverse these abnormal phenotypes.
SSc iPSC was generated from PBMC by Sendai virus. Human iPSC lines from SSc patients were differentiated into dermal fibroblasts and keratinocytes. The iPSC-derived differentiated cells from the SSc patients were used on high-throughput platforms to screen for FDA-approved drugs that could be effective treatments for SSc.
Skin organoids were generated from these cells exhibited fibrosis that resembled SSc skin. Screening of the 770-FDA-approved drug library showed that the anti-osteoporotic drug raloxifene reduced SSc iPSC-derived fibroblast proliferation and extracellular matrix production and skin fibrosis in organoids and bleomycin-induced SSc-model mice.
This study reveals that a disease model of systemic sclerosis generated using iPSCs-derived skin organoid is a novel tool for in vitro and in vivo dermatologic research. Since raloxifene and bazedoxifene are well-tolerated anti-osteoporotic drugs, our findings suggest that selective estrogen receptor modulator (SERM)-class drugs could treat SSc fibrosis.
系统性硬化症（SSc）的罕见性阻碍了这种难治性自身免疫性疾病的治疗发展。诱导多能干细胞（iPSC）可在体外分化为关键的疾病相关细胞。患者来源的 iPSC 的产生为罕见病建模开辟了可能性。由于这些细胞可以重现所研究细胞的疾病表型，因此它们是用于筛选可逆转这些异常表型的药物的高通量平台非常有用。
通过仙台病毒从 PBMC 中生成 SSc iPSC。从 SSc 患者中生成人类 iPSC 系，并将其分化为真皮成纤维细胞和角质形成细胞。使用 SSc 患者来源的 iPSC 分化细胞在高通量平台上筛选可有效治疗 SSc 的 FDA 批准药物。
从这些细胞中生成的皮肤类器官表现出类似于 SSc 皮肤的纤维化。对 770 种 FDA 批准药物库的筛选表明，抗骨质疏松药物雷洛昔芬可减少 SSc iPSC 衍生的成纤维细胞增殖和细胞外基质产生，并减少类器官和博来霉素诱导的 SSc 模型小鼠的皮肤纤维化。
本研究揭示了使用 iPSC 衍生的皮肤类器官生成的系统性硬化症疾病模型是进行体外和体内皮肤科研究的新工具。由于雷洛昔芬和巴多昔芬是耐受性良好的抗骨质疏松药物，我们的发现表明选择性雌激素受体调节剂（SERM）类药物可治疗 SSc 纤维化。
