CD166pos Subpopulation From Differentiated Human ES and iPS Cells Support Repair of Acute Lung Injury

Abstract

Previous efforts to derive lung progenitor cells from human embryonic stem (hES) cells using embryoid body formation or stromal feeder cocultures had been limited by low efficiencies. Here, we report a step-wise differentiation method to drive both hES and induced pluripotent stem (iPS) cells toward the lung lineage. Our data demonstrated a 30% efficiency in generating lung epithelial cells (LECs) that expresses various distal lung markers. Further enrichment of lung progenitor cells using a stem cell marker, CD166 before transplantation into bleomycin-injured NOD/SCID mice resulted in enhanced survivability of mice and improved lung pulmonary functions. Immunohistochemistry of lung sections from surviving mice further confirmed the specific engraftment of transplanted cells in the damaged lung. These cells were shown to express surfactant protein C, a specific marker for distal lung progenitor in the alveoli. Our study has therefore demonstrated the proof-of-concept of using iPS cells for the repair of acute lung injury, demonstrating the potential usefulness of using patient's own iPS cells to prevent immune rejection which arise from allogenic transplantation.

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

“…However, a recent study developed a more efficient differentiation protocol for lung epithelial cells [20]. mRNA expression of type II epithelial markers, such as SPA and SPC, was suppressed in the presence of BSA (Fig.…”

“…Although only ∼9% of iPSCs differentiated into SPC + cells in vitro, transplantation of these unsorted differentiated iPSCs contributed to the reconstitution of BLM-injured lung and significantly reduced BLM-induced lung inflammation and fibrosis in mice. In addition to direct replacement of injured lung epithelia by differentiated iPSCs, homed iPSCs may provide beneficial effects in a paracrine manner [16,20,39]. Current data indicate that diverse paracrine mechanisms exist in stem cell therapy, such as modulation of cytokines, growth factors, and antimicrobial peptides [40].…”

“…Longmire et al [15] used ESCs harboring a new Nkx2-1GFP knock-in reporter to derive primordial lung and thyroid progenitors and purified these progenitors using GFP for expansion in culture. Soh et al [20] reported that lung progenitors could be enriched using the stem cell marker CD166 when differentiated from human ESCs or iPSCs.…”

“…Additionally, they have the potential to overcome the abovementioned limitations. Recently, several studies have reported in vitro differentiation to AEC II-like cells from iPSCs [19,20].…”

Lung cancer stem cells—characteristics, phenotype

“…The urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions (55). uPAR are directly involved in the inhibition of apoptosis and may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies and also possess enhanced clonogenic activity in vitro.…”