Epithelial Cell Differentiation of Human Mesenchymal Stromal Cells in Decellularized Lung Scaffolds

Abstract

Identification of appropriate donor cell types is important for lung cell therapy and for lung regeneration. Previous studies have indicated that mesenchymal stromal cells derived from human bone marrow (hBM-MSCs) and from human adipose tissue (hAT-MSCs) may have the ability to trans-differentiate into lung epithelial cells. However, these data remain controversial. Herein, the ability of hBM-MSCs and hAT-MSCs to repopulate acellular rodent lung tissue was evaluated. hBM-MSCs and hAT-MSCs were isolated from bone marrow aspirate and lipoaspirate, respectively. Rat lungs were decellularized with CHAPS detergent, followed by seeding the matrix with hBM-MSCs and hAT-MSCs. Under appropriate culture conditions, both human MSC populations attached to and proliferated within the lung tissue scaffold. In addition, cells were capable of type 2 pneumocyte differentiation, as assessed by marker expression of surfactant protein C (pro-SPC) at the protein and the RNA level, and by the presence of lamellar bodies by transmission electron microscopy. Additionally, hAT-MSCs contributed to Clara-like cells that lined the airways in the lung scaffolds, whereas the hBM-MSCs did not. We also tested the differentiation potential of MSCs on different extracellular matrix components in vitro, and found that protein substrate influences MSC epithelial differentiation. Together our data show the capacity for human MSCs to differentiate toward lung epithelial phenotypes, and the possibility of using these cells for lung cell therapies and tissue engineering.

Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue

“…MSCs have also been shown to acquire an epithelial cell phenotype in various tissues such as intestine (98, 324), lung (241), and esophagus (172). These processes are mediated by protein substrate-MSC interactions (241) and even cell fusion with native epithelial cells (98).…”

Sodium hydroxide based non-detergent decellularizing solution for rat lung

“…1-4 Retention of extracellular matrix (ECM) components during the decellularized process is crucial for influencing the behavior of cells that are subsequently placed on the decellularized scaffold. 5 ECM components play a major role in the proper migration, protein expression, and active signaling pathways of the donor cells. 6 , 7 Transplantation studies of recellularized lung reveal that the alveolar structure of the bioengineered lung is fragile and the histological integrity of the recellularized lung seems to be determined by damage to the ECM at the thin barrier of the alveoli.…”

Coming to terms with tissue engineering and regenerative medicine in the lung

“…There is now considerable evidence that MSCs play a role in regeneration and repair (61,62,81,91,112,201) and in secretion of growth factors, immune modulators, and other factors that support the idea that MSCs may be better taken up in organ scaffolds (158,198,220), especially if scaffolds enhance their differentiation (86,219), presumably through cell-matrix interactions (64,161,174,232). Several studies have shown that MSCs can attach and proliferate in lung scaffolds (39,117,131,137). For example, MSCs derived from human adipose tissue and bone marrow on decellularized rat lungs express markers of pulmonary epithelial cells (117), although the source of the MSCs may play a role in their local behavior such as cell attachment, migration, and proliferation.…”

“…Several studies have shown that MSCs can attach and proliferate in lung scaffolds (39,117,131,137). For example, MSCs derived from human adipose tissue and bone marrow on decellularized rat lungs express markers of pulmonary epithelial cells (117), although the source of the MSCs may play a role in their local behavior such as cell attachment, migration, and proliferation. MSCs within lungs have also been identified that have the ability to express markers of ATI and ATII cells (73,95,214).…”