R-Spondin2, a Positive Canonical WNT Signaling Regulator, Controls the Expansion and Differentiation of Distal Lung Epithelial Stem/Progenitor Cells in Mice.

Ahmed A Raslan,Jeong Kyo Yoon,Youn Jeong Oh,Yong Ri Jin

doi:10.3390/ijms23063089

Abstract

The lungs have a remarkable ability to regenerate damaged tissues caused by acute injury. Many lung diseases, especially chronic lung diseases, are associated with a reduced or disrupted regeneration potential of the lungs. Therefore, understanding the underlying mechanisms of the regenerative capacity of the lungs offers the potential to identify novel therapeutic targets for these diseases. R-spondin2, a co-activator of WNT/β-catenin signaling, plays an important role in embryonic murine lung development. However, the role of Rspo2 in adult lung homeostasis and regeneration remains unknown. The aim of this study is to determine Rspo2 function in distal lung stem/progenitor cells and adult lung regeneration. In this study, we found that robust Rspo2 expression was detected in different epithelial cells, including airway club cells and alveolar type 2 (AT2) cells in the adult lungs. However, Rspo2 expression significantly decreased during the first week after naphthalene-induced airway injury and was restored by day 14 post-injury. In ex vivo 3D organoid culture, recombinant RSPO2 promoted the colony formation and differentiation of both club and AT2 cells through the activation of canonical WNT signaling. In contrast, Rspo2 ablation in club and AT2 cells significantly disrupted their expansion capacity in the ex vivo 3D organoid culture. Furthermore, mice lacking Rspo2 showed significant defects in airway regeneration after naphthalene-induced injury. Our results strongly suggest that RSPO2 plays a key role in the adult lung epithelial stem/progenitor cells during homeostasis and regeneration, and therefore, it may be a potential therapeutic target for chronic lung diseases with reduced regenerative capability.

Highlights

IntroductionThe lungs are essential organs for gas exchange between the blood and the external atmosphere as well as for immune defense against external pathogens and environmental factors
Our present study shows a previously unknown role of RSPO2 as a canonical WNT signaling regulator in adult lung epithelial stem/progenitor cells and airway regeneration
We found that Rspo2 was expressed in the bronchial epithelium and alveoli (Figure 1A)

Summary

Introduction

The lungs are essential organs for gas exchange between the blood and the external atmosphere as well as for immune defense against external pathogens and environmental factors. The histological complexity and distinct functional features of each region of the lungs are well reflected in the identities of specific resident stem/progenitors [1–4]. In the bronchioles of naphthalene-induced injury model mice, variant club cells located near the neuroendocrine bodies function as stem/progenitor cells [1,3,8]. They can self-renew and differentiate into multiple epithelial lineages, including basal, ciliated, and goblet cells of the airways, and even alveoli type 1 (AT1) and surfactant protein C (SFTPC+ve) type 2 (AT2) cells [1,6,9–12]. The regenerative function of these region-specific stem/progenitor cells is tightly regulated by the cross-talk between them and their microenvironment or neighboring cells [17–20]

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