A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients.
A new platform for high-throughput therapy testing on iPSC-derived lung progenitor cells from cystic fibrosis patients.
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DOI：
10.1016/j.stemcr.2021.09.020
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Bear CE
中科院分区：
文献类型：
--
作者：
Jiang JX;Wellhauser L;Laselva O;Utkina I;Bozoky Z;Gunawardena T;Ngan Z;Xia S;Di Paola M;Eckford PDW;Ratjen F;Moraes TJ;Parkinson J;Wong AP;Bear CE
对于那些携带罕见CFTR突变的囊性纤维化患者，对目前可用的治疗方法没有反应，因此对治疗开发的相关组织模型的需求尚未得到满足。在这里，我们描述了一个新的测试平台，该平台使用患者特异性诱导多能干细胞（iPSCs）分化为肺祖细胞，可以使用基于CFTR通道活性的动态、高通量荧光分析进行研究。我们的概念验证研究支持该平台的潜在用途，以及加拿大生物资源，该生物资源包含iPSC系和来自罕见突变患者的匹配鼻腔培养，以推进面向患者的治疗开发。在高通量、基于干细胞的模型中确定的干预措施，并在同一人的原代鼻腔培养中得到验证，有可能成为先进的治疗方法。来自罕见CFTR突变的人的肺祖细胞（LPCs）可以进行高通量治疗测试。匹配的鼻腔培养可以验证LPCs患者特异性药物反应。Bear和他的同事表明，从囊性纤维化（CF） iPSCs分化出来的肺祖细胞（LPCs）概括了不同类型CF突变所赋予的主要缺陷。LPCs能够对干预措施进行高通量测试，试点研究表明，LPCs的反应可以在患者匹配的原代鼻上皮培养中得到验证，这证实了LPCs在精确CF治疗开发中的潜在效用。
For those people with cystic fibrosis carrying rare CFTR mutations not responding to currently available therapies, there is an unmet need for relevant tissue models for therapy development. Here, we describe a new testing platform that employs patient-specific induced pluripotent stem cells (iPSCs) differentiated to lung progenitor cells that can be studied using a dynamic, high-throughput fluorescence-based assay of CFTR channel activity. Our proof-of-concept studies support the potential use of this platform, together with a Canadian bioresource that contains iPSC lines and matched nasal cultures from people with rare mutations, to advance patient-oriented therapy development. Interventions identified in the high-throughput, stem cell-based model and validated in primary nasal cultures from the same person have the potential to be advanced as therapies. A Canadian resource (CFIT) has CF donor-matched iPSCs and nasal epithelial cells Lung progenitor cells (LPCs) differentiated from iPSCs express CFTR LPCs from people with rare CFTR mutations enable high-throughput therapy testing Matching nasal cultures can validate patient-specific drug responses in LPCs Bear and colleagues show that lung progenitor cells (LPCs) differentiated from cystic fibrosis (CF) iPSCs recapitulate the primary defects conferred by different types of CF mutations. LPCs enable high-throughput testing of interventions, and pilot studies show that responses in LPCs can be validated in patient-matched primary nasal epithelial cultures, confirming the potential utility of LPCs in precision CF therapy development.
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影响因子：
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