Journal
DEVELOPMENT
Volume 149, Issue 20, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200693
Keywords
Lung organoid; Bud tip progenitor; Human pluripotent stem cell; Single cell RNA sequencing
Categories
Funding
- Cystic Fibrosis Foundation Epithelial Stem Cell Consortium
- Chan Zuckerberg Initiative DAF, an advised fund of the Silicon Valley Community Foundation [CZF2019-002440]
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL119215]
- National Institutes of Health Tissue Engineering and Regenerative Medicine Training Grant (NIH-NIDCR) [T32DE007057]
- Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NIH-NHLBI) [F31HL152531]
- T32 Michigan Medical Scientist Training Program [5T32GM007863-40]
- Ruth L. Kirschstein Predoctoral Individual National Research Service Award from the National Institutes of Health (NIH-NHLBI) [F31HL146162]
- University of Michigan Medical School
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This study successfully developed an iPSC organoid model enriched with NKX2-1(+) BTP-like cells. By optimizing the differentiation process and using single cell RNA sequencing analysis, researchers demonstrated a high degree of transcriptional similarity between the induced BTPs (iBTPs) and in vivo BTPs. This model is important for studying human lung development and differentiation.
Bud tip progenitors (BTPs) in the developing lung give rise to all epithelial cell types found in the airways and alveoli. This work aimed to develop an iPSC organoid model enriched with NKX2-1(+) BTP-like cells. Building on previous studies, we optimized a directed differentiation paradigm to generate spheroids with more robust NKX2-1 expression. Spheroids were expanded into organoids that possessed NKX2-1(+)/CPM+ BTP-like cells, which increased in number over time. Single cell RNA-sequencing analysis revealed a high degree of transcriptional similarity between induced BTPs (iBTPs) and in vivo BTPs. Using FACS, iBTPs were purified and expanded as induced bud tip progenitor organoids (iBTOs), which maintained an enriched population of bud tip progenitors. When iBTOs were directed to differentiate into airway or alveolar cell types using well-established methods, they gave rise to organoids composed of organized airway or alveolar epithelium, respectively. Collectively, iBTOs are transcriptionally and functionally similar to in vivo BTPs, providing an important model for studying human lung development and differentiation.
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