monarch-initiative · github-actions · Feb 12, 2026 · Feb 12, 2026
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+# Cystic Fibrosis Research Datasets and Models
+
+**Date**: 2026-02-12
+**Focus Areas**: Single-cell datasets, NAM (New Approach Methodology) models, Physiological models
+
+---
+
+## Executive Summary
+
+This document provides a comprehensive review of cutting-edge datasets and model systems for cystic fibrosis research, prioritizing single-cell genomics, new approach methodologies (NAMs) including organoid systems, and physiological models that recapitulate human CF pathophysiology. These resources enable mechanistic understanding of CF pathogenesis and support personalized medicine approaches.
+
+---
+
+## 1. Single-Cell Datasets
+
+### 1.1 Recent Single-Cell RNA Sequencing Studies (2024-2026)
+
+#### **Pediatric CF Lung Single-Cell Atlas (2026)**
+- **Publication**: Scientific Reports, 2026
+- **Description**: Single-cell transcriptional landscape of the pediatric CF lung from minimally invasive respiratory specimens
+- **Key Findings**: Revealed dysregulated, neutrophil-dominant inflammation and a pro-inflammatory airway epithelium
+- **Sample Source**: Minimally invasive respiratory specimens from pediatric CF patients
+- **Significance**: Provides insights into early-stage CF lung pathology in children
+- **Reference**: [Scientific Reports Article](https://www.nature.com/articles/s41598-026-36125-w)
+
+#### **CF Liver Disease Single-Cell Analysis (2024)**
+- **Publication**: Liver International, June 2024
+- **Description**: Single-cell RNA sequencing of CF liver disease explants
+- **Key Findings**: Revealed endothelial complement activation in CF liver disease
+- **Sample Source**: CF liver disease explants from transplant patients
+- **Significance**: First comprehensive single-cell analysis of CF hepatic complications
+- **PMID**: 38847551
+- **Reference**: [Liver International Article](https://onlinelibrary.wiley.com/doi/10.1111/liv.15963)
+
+#### **Human Fetal Lung Development Atlas (2024)**
+- **Publication**: Nature Communications, July 2024
+- **Description**: Over 150,000 single cells from 19 healthy human fetal lung tissues
+- **Key Findings**: Captured developmental trajectories from progenitor cells expressing CFTR
+- **Sample Source**: Human fetal lung tissues (gestational ages not specified)
+- **Significance**: Provides developmental context for understanding CFTR expression and CF pathogenesis from embryonic origins
+- **Reference**: [Nature Communications Article](https://www.nature.com/articles/s41467-024-50281-5)
+
+### 1.2 Foundational Single-Cell Studies (2021-2023)
+
+#### **Multi-Institute CF Airways Consortium Study (2021)**
+- **Publication**: Nature Medicine, 2021
+- **Description**: Single-cell transcriptional analysis of CF airways at single-cell resolution
+- **Key Findings**:
+  - Compared proximal airways from 19 CF donors (undergoing transplantation) with 19 healthy lung donors
+  - Revealed overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets
+  - Demonstrated decrease in cycling basal cells
+  - Identified altered epithelial cell states and composition
+- **Sample Source**: Proximal airways from transplant donors (CF) and healthy controls
+- **Cell Count**: Comprehensive analysis of airway epithelial populations
+- **Significance**: Landmark study establishing baseline single-cell reference for CF airways
+- **Reference**: [Nature Medicine Article](https://www.nature.com/articles/s41591-021-01332-7)
+
+#### **CF Lung Basic and Translational Insights (2023)**
+- **Publication**: American Journal of Respiratory Cell and Molecular Biology, 2023
+- **Description**: Review of single-cell RNA sequencing insights in CF lung
+- **Key Findings**: Summarized new basic and translational insights from scRNA-seq studies
+- **Significance**: Comprehensive synthesis of single-cell findings in CF research
+- **Reference**: [AJRCMB Article](https://www.atsjournals.org/doi/full/10.1165/rcmb.2022-0038TR)
+
+### 1.3 Computational Resources
+
+#### **CF-Seq Web Application (2022)**
+- **Publication**: Scientific Data, 2022
+- **Description**: Accessible web application for rapid re-analysis of CF pathogen RNA sequencing studies
+- **Functionality**: Enables rapid re-analysis and meta-analysis of CF RNA-seq datasets
+- **Significance**: Democratizes access to CF transcriptomic data analysis
+- **Reference**: [Scientific Data Article](https://www.nature.com/articles/s41597-022-01431-1)
+
+---
+
+## 2. NAM (New Approach Methodology) Models
+
+### 2.1 Intestinal Organoid Models
+
+#### **HIT-CF Organoid Study**
+- **Description**: Stratifying CF patients based on intestinal organoid response to different CFTR-modulators
+- **Methodology**: Forskolin-induced swelling (FIS) assay in rectal organoids
+- **Key Features**:
+  - Generated from rectal biopsies
+  - Enables robust CFTR function measurements
+  - FIS assay accurately predicts treatment efficacy in individual patients
+- **Clinical Application**: Creating access pathway for CFTR-modulating drugs for patients with ultra-rare CFTR variants
+- **Significance**: Enables personalized medicine for patients excluded from classical clinical trials
+- **Reference**: [Translational Medicine Communications](https://transmedcomms.biomedcentral.com/articles/10.1186/s41231-020-00060-3)
+
+#### **Intestinal Organoid Monolayer Models**
+- **Publication**: Life Science Alliance, 2023
+- **Description**: Validating organoid-derived human intestinal monolayers for personalized therapy
+- **Key Features**:
+  - Derived from patient intestinal organoids
+  - Enables high-throughput screening
+  - Maintains CFTR-specific phenotypes
+- **Reference**: [Life Science Alliance Article](https://www.life-science-alliance.org/content/6/6/e202201857)
+
+### 2.2 Nasal Epithelial Organoid Models
+
+#### **Conditionally Reprogrammed Nasal Stem Cells**
+- **Publication**: European Respiratory Journal, 2021
+- **Description**: Theratyping CF in vitro using ALI culture and organoids from patient-derived nasal epithelial conditionally reprogrammed stem cells
+- **Key Features**:
+  - Highly efficient in vitro expansion of airway epithelial stem cells (AESCs)
+  - Generated from minimally invasive nasal brushing
+  - CFTR modulating drug efficacy predicted in personalized manner using 3D airway organoids
+  - Forskolin-induced swelling assay for drug response testing
+- **Significance**: Non-invasive patient-specific model for drug screening
+- **Reference**: [ERJ Article](https://publications.ersnet.org/content/erj/58/6/2100908)
+
+#### **2D-to-3D Nasal Epithelial Model**
+- **Publication**: Life Science Alliance, 2022
+- **Description**: Measuring CF drug responses in organoids derived from 2D differentiated nasal epithelia
+- **Methodology**: Transition from 2D air-liquid interface cultures to 3D organoid format
+- **Significance**: Combines advantages of both culture systems
+- **Reference**: [Life Science Alliance Article](https://www.life-science-alliance.org/content/5/12/e202101320)
+
+### 2.3 Other Tissue-Specific Organoids
+
+#### **Endometrium-Derived Organoids**
+- **Publication**: Cellular and Molecular Life Sciences, 2025
+- **Description**: Endometrium-derived organoids from CF patients and mice
+- **Application**: New models to study disease-associated endometrial pathobiology
+- **Significance**: Expands understanding of CF beyond respiratory and gastrointestinal systems
+- **Reference**: [CMLS Article](https://link.springer.com/article/10.1007/s00018-025-05627-7)
+
+### 2.4 Organ-on-a-Chip Models
+
+#### **CF Organoid-on-a-Chip (OrgOC)**
+- **Publication**: Recent review (2025)
+- **Description**: Integration of organoid technology with microfluidic platforms
+- **Key Features**:
+  - High simulation fidelity
+  - Individualized therapeutic capabilities
+  - Cost-effectiveness
+  - High-throughput screening potential
+- **Significance**: Next-generation platform for CF drug discovery and personalized medicine
+- **Reference**: [ScienceDirect Article](https://www.sciencedirect.com/science/article/pii/S2590006425007185)
+
+---
+
+## 3. Physiological Models
+
+### 3.1 Advanced In Vitro Models
+
+#### **CF Airway-on-a-Chip**
+- **Publication**: Journal of Cystic Fibrosis, 2021
+- **Description**: Modeling pulmonary CF in a human lung airway-on-a-chip
+- **Key Features**:
+  - Faithfully recapitulates features of human CF airways
+  - Enhanced mucus accumulation
+  - Increased cilia density
+  - Higher ciliary beating frequency compared to healthy controls
+- **Significance**: Organ-level physiological modeling in microfluidic device
+- **Reference**: [JCF Article](https://www.cysticfibrosisjournal.com/article/S1569-1993(21)02106-8/fulltext)
+
+#### **Air-Liquid Interface (ALI) Cultures**
+- **Description**: Two- and three-dimensional cell culture models of human CF airway epithelium
+- **Applications**:
+  - Studying mucus production
+  - Inflammatory response modeling
+  - Airway remodeling research
+- **Key Features**:
+  - Better recapitulate native airway epithelium compared to submerged cultures
+  - Polarized differentiated epithelia
+  - Maintained ion channel physiology
+- **Significance**: Standard model for CF airway research
+- **Reference**: [PMC Article](https://pmc.ncbi.nlm.nih.gov/articles/PMC6276497/)
+
+### 3.2 Cell Lines
+
+#### **NuLi-1 and CuFi Cell Lines**
+- **Publication**: American Journal of Physiology-Lung Cellular and Molecular Physiology, 2002
+- **Description**: Development of CF and non-CF airway cell lines
+- **Cell Lines**:
+  - **NuLi-1**: Normal lung epithelial cells
+  - **CuFi-1, CuFi-3, CuFi-4**: CF epithelial cells from various CF genotypes
+- **Key Features**:
+  - Derived from human airway epithelium
+  - Capable of forming polarized differentiated epithelia at air-liquid interface
+  - Exhibit transepithelial resistance
+  - Maintain genotype-specific ion channel physiology
+- **Significance**: Immortalized cell lines enabling reproducible CF research
+- **Reference**: [AJP-Lung Article](https://journals.physiology.org/doi/full/10.1152/ajplung.00355.2002)
+
+### 3.3 Co-Culture Models
+
+#### **Multi-Cell Type Co-Cultures**
+- **Description**: Co-cultures of airway epithelial cells with immune and stromal cells
+- **Components**:
+  - Airway epithelial cells
+  - Macrophages
+  - Dendritic cells
+  - Fibroblasts
+- **Applications**:
+  - Disease modeling
+  - Drug discovery
+  - Identification of novel therapeutic targets
+- **Significance**: Recapitulates complex cellular interactions in CF airways
+- **Reference**: [Analytical Cellular Pathology Review](https://onlinelibrary.wiley.com/doi/10.1155/2018/3839803)
+
+### 3.4 Advanced Scaffold-Based Models
+
+#### **3D Scaffold and Cell Sheet Technology**
+- **Description**: Sophisticated models based on scaffold materials and cell sheet technology
+- **Key Features**:
+  - Recapitulate tissue- and organ-level physiology
+  - Enable long-term culture
+  - Better mimic in vivo architecture
+- **Significance**: Bridge between 2D cultures and in vivo studies
+
+### 3.5 Animal Models
+
+#### **Large Animal CF Models**
+- **Species**: Rat, ferret, pig
+- **Key Features**:
+  - Demonstrate range of well-characterized lung disease phenotypes
+  - Varying degrees of severity
+  - More closely recapitulate human CF lung disease than mouse models
+- **Limitations of Mouse Models**: CF mice do not exhibit severe pathology characteristic of established human CF lung disease (chronic respiratory infection, inflammation, mucus plugging, progressive bronchiectasis)
+- **Significance**: Essential for preclinical therapeutic development
+- **Reference**: [Respiratory Research Article](https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0750-y)
+
+---
+
+## 4. Key Mechanistic Insights from Models
+
+### 4.1 Airway Surface Liquid Pathophysiology
+- Dehydrated secretions due to CFTR dysfunction
+- Impaired mucociliary clearance
+- Role of submucosal glands in disease progression
+- **Reference**: [AJP-Cell Physiology](https://journals.physiology.org/doi/full/10.1152/ajpcell.00417.2002)
+
+### 4.2 Epithelial Cell Dysfunction
+- Central role in innate immune responses
+- Involvement in mucociliary clearance
+- Pathogen sensing and inflammatory response orchestration
+- Activation of mesenchymal cells
+- **Reference**: [PMC Article on Airway Epithelium](https://pmc.ncbi.nlm.nih.gov/articles/PMC5911336/)
+
+### 4.3 Pathogenic Features Modeled
+- Chronic inflammation
+- Oxidative stress
+- Mucus plugging
+- Airway remodeling
+- Respiratory infections
+- **Reference**: [PMC Pathogenesis Review](https://pmc.ncbi.nlm.nih.gov/articles/PMC2430075/)
+
+---
+
+## 5. Clinical Translation and Personalized Medicine
+
+### 5.1 Theratyping Applications
+Organoid models enable patient-specific drug response prediction:
+- **FIS Assay**: Forskolin-induced swelling correlates with clinical efficacy
+- **Rare Variant Testing**: Patients with ultra-rare CFTR variants can access modulators based on organoid response
+- **Precision Medicine**: Treatment decisions guided by individual organoid drug responses
+
+### 5.2 High-Throughput Screening
+NAM models enable:
+- Cost-effective drug screening
+- Rapid compound testing
+- Personalized therapeutic selection
+- Reduced reliance on animal models
+
+---
+
+## 6. Recommendations for Dataset Integration
+
+### 6.1 Priority Datasets for Integration
+1. **Nature Medicine 2021 single-cell atlas** (19 CF vs 19 healthy donors) - foundational reference
+2. **Scientific Reports 2026 pediatric study** - developmental insights
+3. **HIT-CF organoid study** - personalized medicine validation
+
+### 6.2 Model Systems for Experimental Validation
+1. **Nasal epithelial organoids** - patient-accessible, non-invasive
+2. **Airway-on-a-chip** - physiological fidelity
+3. **Intestinal organoids with FIS** - clinical correlation validated
+
+### 6.3 Complementary Resources
+1. **CF-Seq web application** - for meta-analysis
+2. **NuLi-1/CuFi cell lines** - for mechanism studies
+3. **Large animal models** (ferret, pig) - for preclinical validation
+
+---
+
+## 7. Future Directions
+
+### 7.1 Multi-Omics Integration
+- Combine single-cell transcriptomics with proteomics and metabolomics
+- Spatial transcriptomics in CF tissues
+- Integration of genetic variant data with functional organoid responses
+
+### 7.2 Advanced NAMs
+- Vascularized organoid models
+- Multi-organ-on-chip systems (lung-liver-intestine)
+- Incorporation of immune cell components
+
+### 7.3 AI/ML Applications
+- Predictive modeling of drug responses from organoid data
+- Single-cell data integration for patient stratification
+- Image-based phenotyping of organoid responses
+
+---
+
+## Sources
+
+### Single-Cell Datasets
+- [CF-Seq Web Application - Scientific Data 2022](https://www.nature.com/articles/s41597-022-01431-1)
+- [Single-Cell RNA Sequencing Insights - PMC 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC9986558/)
+- [Single-Cell RNA Sequencing Review - AJRCMB 2023](https://www.atsjournals.org/doi/full/10.1165/rcmb.2022-0038TR)
+- [CF Liver Disease scRNA-seq - Liver International 2024](https://onlinelibrary.wiley.com/doi/10.1111/liv.15963)
+- [CF Airways Single-Cell Analysis - Nature Medicine 2021](https://www.nature.com/articles/s41591-021-01332-7)
+- [Pediatric CF Lung Single-Cell Atlas - Scientific Reports 2026](https://www.nature.com/articles/s41598-026-36125-w)
+- [Fetal Lung Development Atlas - Nature Communications 2024](https://www.nature.com/articles/s41467-024-50281-5)
+
+### NAM Models
+- [Theratyping with Nasal Organoids - ERJ 2021](https://publications.ersnet.org/content/erj/58/6/2100908)
+- [2D-to-3D Nasal Model - Life Science Alliance 2022](https://www.life-science-alliance.org/content/5/12/e202101320)
+- [HIT-CF Organoid Study - Translational Medicine Communications](https://transmedcomms.biomedcentral.com/articles/10.1186/s41231-020-00060-3)
+- [Organoid Technology Review - PMC 2023](https://pmc.ncbi.nlm.nih.gov/articles/PMC9856584/)
+- [Organoid-on-a-Chip - ScienceDirect 2025](https://www.sciencedirect.com/science/article/pii/S2590006425007185)
+- [Endometrium Organoids - CMLS 2025](https://link.springer.com/article/10.1007/s00018-025-05627-7)
+- [Intestinal Organoids Review - ERJ 2019](https://publications.ersnet.org/content/erj/54/1/1802379)
+- [Intestinal Monolayers - Life Science Alliance 2023](https://www.life-science-alliance.org/content/6/6/e202201857)
+
+### Physiological Models
+- [Human Cellular Models Review - PMC 2018](https://pmc.ncbi.nlm.nih.gov/articles/PMC6276497/)
+- [Airway Surface Liquid Role - AJP-Cell 2003](https://journals.physiology.org/doi/full/10.1152/ajpcell.00417.2002)
+- [CF Pathogenesis Mechanisms - PMC 2008](https://pmc.ncbi.nlm.nih.gov/articles/PMC2430075/)
+- [CF Cell Line Development - AJP-Lung 2003](https://journals.physiology.org/doi/full/10.1152/ajplung.00355.2002)
+- [Airway Epithelium Dysfunction - PMC 2018](https://pmc.ncbi.nlm.nih.gov/articles/PMC5911336/)
+- [CF Airway-on-a-Chip - JCF 2022](https://www.cysticfibrosisjournal.com/article/S1569-1993(21)02106-8/fulltext)
+- [Animal Models of CF - Respiratory Research 2018](https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0750-y)
+
+---
+
+**Document Version**: 1.0
+**Last Updated**: 2026-02-12
+**Compiled by**: Dragon AI Agent (@dragon-ai-agent)
+**Requested by**: @cmungall (GitHub Issue #302)