The long and winding road: stem cells for cystic fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF) is a genetic syndrome with a high mortality rate due to severe lung disease. Despite having several drugs targeting specific mutated CFTR proteins already in clinical trials, new therapies, based on stem cells, are also emerging to treat those patients.

Areas covered: The authors review the main sources of stem cells, including embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs), gestational stem cells, and adult stem cells, such as mesenchymal stem cells (MSCs) in the context of CF. Furthermore, they describe the main animal and human models of lung physiology and pathology, involved in the optimization of these stem cell-applied therapies in CF.

Expert opinion: ESCs and iPSCs are emerging sources for disease modeling and drug discovery purposes. The allogeneic transplant of healthy MSCs, that acts independently to specific mutations, is under intense scrutiny due to their secretory, immunomodulatory, anti-inflammatory and anti-bacterial properties. The main challenge for future developments will be to get exogenous stem cells into the appropriate lung location, where they can regenerate endogenous stem cells and act as inflammatory modulators. The clinical application of stem cells for the treatment of CF certainly warrants further insight into pre-clinical models, including large animals, organoids, decellularized organs and lung bioengineering.

KEYWORDS:

• Cystic fibrosis transmembrane conductance regulator
• embryonic stem cells
• induced pluripotent stem cells
• mesenchymal stem cells
• organoids
• decellularized lungs
• bioengineered lungs

Article highlights

• Cystic fibrosis (CF) is a life-threatening autosomal recessive disorder due to mutations in the CF transmembrane conductance regulator (CFTR) gene, with clinical manifestations in the lung, pancreas, liver, and the gut. Accumulation of sticky mucus in these organs leads to infection with opportunistic bacteria, devastating inflammation and ensuing tissue damage.

• CF is without cure, although novel drugs targeting the basic molecular defect in the CFTR protein, accordingly to the mutation class, are being introduced in the clinic. Nevertheless, CF is a disease susceptible to be treated with stem cell-based treatments due to its pathological features and because this approach can be used independently of mutation class.

• Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), can regenerate epithelial cells belonging to the airways, biliary ductules and exocrine pancreas, nevertheless they are envisioned today as a platform for drug screening and investigation of disease mechanisms.

• Mesenchymal stem cells (MSCs), obtained from various adult tissues, are the most studied for their regenerative, anti-inflammatory, anti-bacterial and immunomodulatory capacities.

• Gestational stem cells, such as amniotic mesenchymal stem cells, can correct the CFTR functional defect in co-culture with CF airway epithelial cells, and they could lead to the resolution of the CF-associated basic defects even in vivo.

The promises of stem cell-based therapies will not be fulfilled until preclinical models, such as large animal models, organoids, decellularized lungs and bioengineered organs will be profitably used, paving the way to a meaningful clinical application.

Acknowledgments

We thank Vincenzo Giambra for critically reading of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This manuscript is supported by the Italian law on cystic fibrosis (L. 548/93). Furthermore, S Castellani is a researcher funded by the Intervento Cofinanziato dal Fondo di Sviluppo e Coesione 2007-2013 - APQ Ricerca Regione Puglia ‘Programma regionale a sostegno della specializzazione intelligente e delle sostenibilità sociale ed ambientali - Future in Research’.