Autologous transplantation of lung progenitor cells comes into reality for bronchiectasis

Abstract

Stem and progenitor cell-based regenerative therapies have the potential to cure chronic respiratory diseases. Yan et al.¹ reported a clinical trial of autologous P63⁺ progenitor cell transplantation in bronchiectasis patients, highlighting autologous transplantation of P63⁺ progenitor cells as a novel candidate therapeutic option to improve pulmonary gas exchange function and quality of life.

Stem and progenitor cell-based regenerative therapies have the potential to cure chronic respiratory diseases. Yan et al. reported a clinical trial of autologous P63⁺ progenitor cell transplantation in bronchiectasis patients, highlighting autologous transplantation of P63⁺ progenitor cells as a novel candidate therapeutic option to improve pulmonary gas exchange function and quality of life.

Main text

Bronchiectasis is a common chronic respiratory disease characterized by the pathological dilatation and recurrent infection of airways. The relentless inflammatory responses are responsible for airway structural damage. Despite the increasing global prevalence of bronchiectasis,² existing treatments for bronchiectasis (e.g., infection control, mucus clearance) mainly target symptomatic management.³ There remains, unfortunately, a paucity of effective therapeutic options to halt the progression of or even reverse respiratory structural damage. It is imperative to develop novel treatment modalities that could slow the decline in lung function and repair the already-damaged airway structures among patients with bronchiectasis.

Significant advancements have been achieved in the field of regenerative medicine and stem cell biology over the past few decades. Stem cell therapies represent the multimodal therapeutic agents that modulate both the immune and regenerative functions and are a promising therapeutic strategy for lung injury repair.⁴ In adults, the lungs contain various types of epithelial stem cells or progenitor cells that maintain lung homeostasis and repair damaged lung tissue. P63⁺ progenitor cells in mice and humans exhibit a potent regenerative response to lung injury, thereby facilitating airway epithelial reconstruction and promoting repair and regeneration of the alveoli.⁵ Zuo et al. showed that rare preexisting distal airway stem cell-population-expressing P63 and KRT5 pedigrees contribute multiple epithelial lineages to regenerating distal lung and play essential roles in promoting murine lung repair after influenza-induced acute injury.⁶ In another study, researchers successfully isolated and expanded the SOX9⁺/P63⁺/KRT5⁺ airway basal cells from a minimal sample of lung tissue obtained through a bronchoscopic brushing procedure. The SOX9⁺/P63⁺/KRT5⁺ airway basal cells were transplanted into an immunodeficient mouse with lung injuries, which subsequently regenerated the functional lung epithelium and reconstructed the bronchial epithelial cells and alveolar cells. A clinical trial involving autologous basal cell transplantation in two bronchiectasis patients has demonstrated significant improvements in lung tissue repair and improved lung function within 3–12 months following transplantation.⁷ These findings suggested that autologous stem cell transplantation may be beneficial in bronchiectasis.

The reality of stem cell therapy for bronchiectasis has now come into testing in clinical practice. In this issue of Cell Reports Medicine, Yan et al. successfully cloned and expanded the P63⁺ progenitor cells from the airway brushing tissues of bronchiectasis patients and conducted a randomized, single-blind, controlled, phase 1/2 trial to evaluate the safety and efficacy of autologous P63⁺ progenitor cell transplantation in bronchiectasis patients (ClinicalTrials.gov; NCT03655808).¹ The researchers examined the abundance and distribution of P63⁺KRT5⁺ cells in lung tissue samples obtained from patients with bronchiectasis and observed a higher prevalence of this cell type among newly diagnosed individuals or those without recent active infections, providing compelling evidence for the successful acquisition of autologous P63⁺ progenitor cells in bronchiectasis patients. They also found that autologous P63⁺ progenitor cell transplantation could significantly improve the gas exchange capacity, as evidenced by the significant elevated diffusing capacity of the lungs for carbon monoxide (D_LCO) (Figure 1). This finding was consistent with the results of an autologous P63⁺ progenitor cell transplant for patients with chronic obstructive pulmonary disease (COPD).⁸

Figure 1.

Autologous transplantation of P63⁺ lung progenitor cells in patients with bronchiectasis

BSI, bronchiectasis severity index; FACED, an acronym derived from five variables (F: forced expiratory volume in one second; A: age; C: chronic colonization by Pseudomonas aeruginosa; E: radiological extension [number of pulmonary lobes affected]; and D: dyspnea).

Furthermore, the authors showed that patients in the transplantation group demonstrated significantly reduced lung damaged area, improved quality of life, and lower Bronchiectasis Severity Index and FACED scores within approximately 4–12 weeks following treatment (Figure 1). In addition, transcriptomic analysis of the cells from different patients showed that progenitor cells with upregulated P63 gene expression demonstrated more favorable therapeutic efficacy. Taken together, the results show that transplantation of autologous P63⁺ progenitor cells is effective and safe for bronchiectasis patients.

The study findings are clinically relevant and promising. The autologous transplantation of P63⁺ lung progenitor cells may restore airway structural integrity in bronchiectasis. Previous studies have revealed that in the lung lesions of people with COPD and cystic fibrosis, stem cells undergo pathological changes that lead to chronic inflammation and unresolved pulmonary damage.^9,10 Therefore, targeted therapy at the stem cell level may be essential to the treatment of chronic respiratory diseases, as confirmed by the findings of Yan et al. in bronchiectasis.

While the study has shown promising results, some questions need to be addressed. First, the generalizability of the findings should be further tested in a study with larger sample sizes and multi-center study designs. It would be interesting to determine whether autologous cell transplantation would be equally effective among patients with severe gas exchange dysfunction. Stratification of the underlying causes and disease severity may help unveil the patient subpopulation that may benefit more from the therapy. A longer follow-up will provide sufficient evidence to evaluate the long-term safety and efficacy, particularly in terms of exacerbation frequency and overall mortality.

Despite the challenges for genetic editing of the stem cells and optimization of the cell sources and delivery methods, cell therapy represents an innovative strategy for chronic respiratory diseases that cannot be reversed by conventional therapy. Fortunately, the preliminary data of the current phase 1/2 trial are promising. Further optimization of the cell transplantation therapy among patients with bronchiectasis needs to be explored in phase 3 clinical trials. Cellular regenerative therapy has now come into reality as a better cure for debilitating airway diseases such as bronchiectasis.

Acknowledgments

The authors were supported by the National Natural Science Foundation - Outstanding Youth Fund (no. 82222001), the R&D Program of Guangzhou National Laboratory (no. GZNL2024A02003), the National Natural Science Foundation (no. 82470040), the National Natural Science Foundation (no. 81870003), the Guangzhou Science and Technology Plans (no. 2024A04J6495, 2024A03J1206, 2023B03J0407, 202102010372), the Guangdong Science and Technology Foundation (no. 2019B030316028), and the Zhongnanshan Medical Foundation of Guangdong Province (no. ZNSA-2020013).

Declaration of interests

The authors declare no competing interests.