Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.,Cell Stem Cell

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Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2017-09-28 , DOI: 10.1016/j.stem.2017.08.014
Anjali Jacob ₁ , Michael Morley ₂ , Finn Hawkins ₁ , Katherine B McCauley ₁ , J C Jean ₁ , Hillary Heins ₃ , Cheng-Lun Na ₄ , Timothy E Weaver ₄ , Marall Vedaie ₁ , Killian Hurley ₁ , Anne Hinds ₅ , Scott J Russo ₂ , Seunghyi Kook ₆ , William Zacharias ₂ , Matthias Ochs ₇ , Katrina Traber ₅ , Lee J Quinton ₅ , Ana Crane ₈ , Brian R Davis ₈ , Frances V White ₃ , Jennifer Wambach ₃ , Jeffrey A Whitsett ₄ , F Sessions Cole ₃ , Edward E Morrisey ₂ , Susan H Guttentag ₆ , Michael F Beers ₂ , Darrell N Kotton ₁

Affiliation

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Pediatrics, Monroe Carell Jr. Children's Hospital, Vanderbilt University, Nashville, TN 37232, USA.
Institute of Functional and Applied Anatomy, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), REBIRTH Cluster of Excellence, 30625 Hannover, Germany.
Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.

Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial "alveolospheres" in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB121ins2) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung.

中文翻译：

人多能干细胞分化为功能性肺泡上皮细胞。

肺泡是呼吸空气的生物所特有的，从多能干细胞（PSC）生成肺泡一直具有挑战性，部分原因是可用于提供体外分化所需的发育路线图的模型系统有限。在这里，我们报告了从人类 PSC 中产生肺泡上皮 2 型细胞 (AEC2)，即肺泡的兼性祖细胞。当人类 SFTPC+ 肺泡祖细胞响应 Wnt 和 FGF 信号传导而从内胚层前体中出现时，我们使用彩色荧光报告线来跟踪和纯化它们。纯化的 PSC 衍生 SFTPC+ 细胞在 3D 培养物中形成单层上皮“肺泡球”，无需间充质支持，表现出自我更新能力，并表现出额外的 AEC2 功能能力。对源自携带纯合表面活性剂突变 (SFTPB121ins2) 的患者的 PSC 进行基于无足迹 CRISPR 的基因校正，可恢复 AEC2 中的表面活性剂处理。因此，PSC 衍生的 AEC2 为疾病建模和远端肺的未来功能再生提供了一个平台。

更新日期：2017-09-29

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