Induced pluripotent stem cell-derived lung alveolar epithelial type II cells reduce damage in bleomycin-induced lung fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis is a chronic, progressive, and severe disease with a limited response to currently available therapies. Epithelial cell injury and failure of appropriate healing or regeneration are central to the pathogenesis of idiopathic pulmonary fibrosis. The purpose of this study is to investigate whether intratracheal transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can stop and reverse the fibrotic process in an experimental model of bleomycin-induced lung fibrosis in rats. Methods: Human induced pluripotent stem cells were differentiated to alveolar type II-like cells and characterized. Lung fibrosis was induced in rats by a single intratracheal instillation of bleomycin. Animals were transplanted with human induced pluripotent stem cells differentiated to alveolar type II-like cells at a dose of 3 × 10 6 cells/animal 15 days after endotracheal bleomycin instillation when the animal lungs were already fibrotic. Animals were sacrificed 21 days after the induction of lung fibrosis. Lung fibrosis was assessed by hydroxiprolin content, histologic studies, and the expression of transforming growth factor-β and α-smooth muscle actin. Results: Cell transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can significantly reduce pulmonary fibrosis and improve lung alveolar structure, once fibrosis has already formed. This is associated with the inhibition of transforming growth factor-β and α-smooth muscle actin in the damaged rat lung tissue. Conclusion: To our knowledge, this is the first data to demonstrate that at the fibrotic stage of the disease, intratracheal transplantation of human induced pluripotent differentiated to alveolar type II-like cells halts and reverses fibrosis.

Improved Alveolar Dynamics and Structure After Alveolar Epithelial Type II Cell Transplantation in Bleomycin Induced Lung Fibrosis

“…Previously, Serrano-Mollar et al demonstrated, in preclinical studies, that AE2C intratracheal transplantation was able to reduce fibrosis and restore pulmonary surfactant proteins levels ( 18 , 19 ). They also observed that the induced pluripotent stem cells (iPSCs) derived AE2C reduce fibrosis by inhibiting TGF-β and α-SMA expression ( 23 ). Furthermore, in a clinical study performed with IPF patients, the intratracheal administration of heterologous AE2C was safe, well-tolerated and with no relevant side effects.…”

Alveolar Type II Cells or Mesenchymal Stem Cells: Comparison of Two Different Cell Therapies for the Treatment of Acute Lung Injury in Rats

“…In general, obtaining and maintaining MSCs in cell culture is much easier compared to ATII [ 62 , 63 ]. MSCs can be isolated from several adult tissues and from fetal tissues, while ATII cells are acquired from an adult´s healthy donor lungs or can be derived in vitro from pluripotent cells [ 35 , 62 ]. Due to the MSC immune-privileged behavior, it is possible an autologous or allogenic treatment that avoids the use of immunosuppression in patients [ 16 , 62 ].…”

“…MSCs are easier to obtain than ATII, which need to be isolated from healthy death lung donors. Nowadays, ATII can also be obtained by the differentiation of adult pluripotent cells in vitro [ 31 , 32 , 33 , 34 , 35 ]. Both cell types were tested in clinical trials for several lung diseases, with a good safety record in patients [ 36 , 37 , 38 , 39 , 40 , 41 ].…”

Evolution of Diploid Progenitor Lung Cell Applications: From Optimized Biotechnological Substrates to Potential Active Pharmaceutical Ingredients in Respiratory Tract Regenerative Medicine

“…Technical problems, such as high individual treatment doses (e.g., several million cells/kg) and treatment administration logistics have been reported, limiting the easy and widespread use of such approaches [83,84]. Noteworthy alternatives yet parallel approaches to stem or progenitor cell therapy consist of the functional restoration of normal resident lung progenitor cells (e.g., ATII cells) using various approaches or the therapeutic use of induced pluripotent stem cell (iPSC) technology for the management of diverse lung injuries (e.g., caused by chemical aggression or hyperoxia) [100][101][102][103].…”