Rescue of murine silica-induced lung injury and fibrosis by human embryonic stem cells

Abstract

Alveolar type II pneumocytes (ATII cells) are considered putative alveolar stem cells. Since no treatment is available to repair damaged epithelium and prevent lung fibrosis, novel approaches to induce regeneration of injured alveolar epithelium are desired.The objective of this study was to assess both the capacity of human embryonic stem cells (HUES-3) to differentiate in vitro into ATII cells and the ability of committed HUES-3 cells (HUES-3-ATII cells) to recover in vivo a pulmonary fibrosis model obtained by silica-induced damage.In vitro differentiated HUES-3-ATII cells displayed an alveolar phenotype characterised by multilamellar body and tight junction formation, by the expression of specific markers such as surfactant protein (SP)-B, SP-C and zonula occludens (ZO)-1 and the activity of cystic fibrosis transmembrane conductance regulator-mediated chloride ion transport.After transplantation of HUES-3-ATII cells into silica-damaged mice, histological and biomolecular analyses revealed a significant reduction of inflammation and fibrosis markers along with lung function improvement, weight recovery and increased survival. The persistence of human SP-C, human nuclear antigen and human DNA in the engrafted lungs indicates that differentiated cells remained engrafted up to 10 weeks.In conclusion, cell therapy using HUES-3 cells may be considered a promising approach to lung injury repair.

Differentiation of Mouse Induced Pluripotent Stem Cells Into Alveolar Epithelial Cells In Vitro for Use In Vivo

“…Although some studies have demonstrated the therapeutic potential of bone marrow-derived stem cells in rodent lung injury models [23,[26][27][28], there is no evidence of a role for these stem cells in populating the lung alveolar epithelium in vivo [29][30][31][32]. Recent studies have reported efficient and direct derivation of lung alveolar epithelium from murine embryonic stem cells (ESCs) [10,11,14,16] for in vitro and in vivo applications. However, immune reactions and ethical issues represent barriers to their clinical application.…”

“…Embryonic stem cells (ESCs) are self-renewing pluripotent cells that can differentiate into alveolar epithelial cells in vitro [5][6][7][8][9][10][11][12][13][14][15][16]. The problems of immune rejection and ethical issues restrict clinical application of ESCs.…”

The pathogenesis of pulmonary fibrosis: a moving target

“…Recently, a study from SPITALIERI et al [110] has shown that HUES-3 can differentiate in vitro in ATII cells. Furthermore, transplantation of HUES-3-ATII into silica damaged mice significantly reduced markers of inflammation and fibrosis.…”

Stem cell therapy for idiopathic pulmonary fibrosis: How far are we from the bench to the bedside?

“…The anti-inflammatory and anti-fibrotic capabilities are also presented in amnion epithelial cells, placenta-derived cells, umbilical cord mesenchymal stem cells and adiposederived stem cells (ADSCs) [53][54][55][56][57][58][59]. Interestingly, ESC engraftment also ameliorates experimental pulmonary fibrosis, although clinical research using ESCs is forbidden at the current time [60,61].…”