Targeting p16INK4a Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury

• DOI: 10.1164/rccm.201908-1573oc
• Publication Date: 2020-07-06T17:42:03Z
• Authors: Maéva Zysman; Bruno Ribeiro Bap...; Laure-Aléa Essari; Sara Taghizadeh; Charlotte Thibaul...; Clément Giffard; Amelle Issa; Marie-Laure Franc...; Marielle Breau; Rachid Souktani; Abdel Aissat; Laurence Caeymaex; Muriel Lizé; Jeanne Tran Van N...; Camille Jung; Robert Rottier; Marcio Do Cruzeiro; Serge Adnot; Ralph Epaud; François Chabot; Sophie Lanone; Jorge Boczkowski; Laurent Boyer
• Keywords: Hyperoxia; Bronchopulmonary Dysplasia

Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether cell-cycle inhibitor p16INK4a limits newborn bronchopulmonary dysplasia (BPD), a condition characterized by arrest alveolar development, leading sequelae.Methods: We exposed p16INK4a-/- p16INK4aATTAC (apoptosis through targeted activation caspase 8) transgenic mice postnatal hyperoxia, followed pneumonectomy mice. measured in blood mononuclear cells preterm newborns, 7- 15-year-old survivors BPD, patients with BPD.Measurements Main Results: concentrations increased fibroblasts hyperoxia-induced BPD persisted into adulthood. deficiency did not protect against hyperoxic lesions pups but promoted restoration architecture Curative clearance p16INK4a-positive once were established restored neutral lipid synthesis lipofibroblast type 2 (AT2) cell development within stem-cell niche. Besides, lipofibroblasts support self-renewal AT2 alveolospheres. Induction PPARγ (peroxisome proliferator-activated receptor γ) agonist hyperoxia also numbers hyperoxia-exposed After pneumonectomy, again led an increase contralateral lung. Finally, we observed mRNA overexpression which older BPD.Conclusions: These data demonstrate potential targeting promoting stimulate from childhood