Amniotic MSCs reduce pulmonary fibrosis by hampering lung B-cell recruitment, retention, and maturation.

Anna Cargnoni,Patrizia Bonassi Signoroni,Francesca R Stefani,Marta Magatti,Antonietta R Silini,Serafina Farigu,Valentina Cesari,Pietro Romele,Ornella Parolini,Elsa Vertua,Ivan Toschi

doi:10.1002/sctm.20-0068

Abstract

Growing evidence suggests a mechanistic link between inflammation and the development and progression of fibrotic processes. Mesenchymal stromal cells derived from the human amniotic membrane (hAMSCs), which display marked immunomodulatory properties, have been shown to reduce bleomycin‐induced lung fibrosis in mice, possibly by creating a microenvironment able to limit the evolution of chronic inflammation to fibrosis. However, the ability of hAMSCs to modulate immune cells involved in bleomycin‐induced pulmonary inflammation has yet to be elucidated. Herein, we conducted a longitudinal study of the effects of hAMSCs on alveolar and lung immune cell populations upon bleomycin challenge. Immune cells collected through bronchoalveolar lavage were examined by flow cytometry, and lung tissues were used to study gene expression of markers associated with different immune cell types. We observed that hAMSCs increased lung expression of T regulatory cell marker Foxp3, increased macrophage polarization toward an anti‐inflammatory phenotype (M2), and reduced the antigen‐presentation potential of macrophages and dendritic cells. For the first time, we demonstrate that hAMSCs markedly reduce pulmonary B‐cell recruitment, retention, and maturation, and counteract the formation and expansion of intrapulmonary lymphoid aggregates. Thus, hAMSCs may hamper the self‐maintaining inflammatory condition promoted by B cells that continuously act as antigen presenting cells for proximal T lymphocytes in injured lungs. By modulating B‐cell response, hAMSCs may contribute to blunting of the chronicization of lung inflammatory processes with a consequent reduction of the progression of the fibrotic lesion.

Highlights

We and others have reported that cells derived from the amniotic membrane of human term placenta, such as amniotic epithelial cells and amniotic mesenchymal stromal cells[5,6,7,8,9,10] and related secretome,[11,12,13] can prevent and reduce the progression of pulmonary fibrosis when injected in bleomycin-instilled rodents, a model which closely resembles human idiopathic pulmonary fibrosis (IPF).[14]
To investigate a possible link between the immune-modulatory properties of hAMSCs and their ability to limit the progression of lung fibrosis, we studied the capacity of hAMSCs to reduce bleomycininduced recruitment of inflammatory cells into alveolar spaces and lung tissue, as well as their polarization and maturation
We investigated if amniotic mesenchymal stromal cells isolated from human term placenta interfere with the inflammatory response in a mouse model of pulmonary fibrosis

Summary

| INTRODUCTION

The pathogenesis of idiopathic pulmonary fibrosis (IPF) is still poorly understood, heavily contributing to the lack of an effective cure. We and others have reported that cells derived from the amniotic membrane of human term placenta, such as amniotic epithelial cells and amniotic mesenchymal stromal cells (hAMSCs)[5,6,7,8,9,10] and related secretome,[11,12,13] can prevent and reduce the progression of pulmonary fibrosis when injected in bleomycin-instilled rodents, a model which closely resembles human IPF.[14] Amniotic cells and their secreted factors possess in vitro and in vivo immune-modulatory properties.

| Ethics statement

Significance statement

| RESULTS

Findings

| DISCUSSION

| CONCLUSION