Epithelial cell differentiation of human mesenchymal stromal cells
Inventors
Niklason, Laura E. • MENDEZ, Julio J.
Assignees
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Publication Number
US-12404495-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The present invention relates to the discovery that different stem cell types (e.g., bone marrow-derived mesenchymal stem cells (RM-MSC) and adipose-derived mesenchymal stem cells (AT-MSC)) undergo large changes in lung epithelial marker 5 expression depending on the substrate on which they are cultured. The present invention includes methods and compositions for differentiating of mesenchymal stem cells, such as bone marrow and adipose tissue mesenchymal stem cells, into lung cells, populations of lung cells, and methods of alleviating or treating a lung defect in a subject in need thereof.
Core Innovation
Human bone marrow- and adipose-derived mesenchymal stromal cells change lung epithelial marker expression in a substrate-dependent manner. When cultured on decellularized lung scaffolds in small airway growth medium, bone marrow-derived mesenchymal stromal cells preferentially adopt type 2 pneumocyte features, including pro-SPC and lamellar bodies, with surfactant protein C secretion and a subset becoming cytokeratin-5+.
Adipose-derived mesenchymal stromal cells cultured under similar decellularized lung scaffold and small airway growth medium conditions produce pro-SPC and Clara-like CCSP+ airway lining cells. In contrast, the adipose-derived mesenchymal stromal cells do not become cytokeratin-5+ in this context, yielding epithelial lung cells characterized by CCSP expression and cytokeratin-5 exclusion.
Matrix coating and extracellular matrix composition further alter epithelial marker percentages, including CCSP, pro-SPC, and cytokeratin-5. Lung extracellular matrix is described as distinct from non-lung scaffolds such as decellularized liver matrix, which fails to induce the same epithelial marker suite.
Claims Coverage
The partial content provided includes one independent claim focused on a Clara-cell dominant epithelial lung cell population derived from adipose tissue-derived mesenchymal stem cells on a substrate. The inventive features explicitly recited in the independent claim are then narrowed or further defined by dependent claims in the provided list.
Clara-cell dominant epithelial lung cell population from AT-MSC differentiation
A population of epithelial lung cells differentiated from adipose tissue-derived mesenchymal stem cells in which the epithelial lung cells comprise at least 95% Clara cells.
CCSP expression without cytokeratin-5
The epithelial lung cells express at least one epithelial marker comprising CCSP and do not express cytokeratin-5.
Decellularized lung tissue substrate
The epithelial lung cells are seeded on a substrate made from decellularized lung tissue.
Ecm composition within the substrate
The extracellular matrix includes one or more of human ECM, laminin, fibronectin, collagen IV, and collagen I.
Genetically modified epithelial lung cell population
The population comprises genetically modified cells.
Therapeutic gene expressed in epithelial lung cells
The genetically modified cells are epithelial lung cells genetically modified to express a therapeutic gene.
Ex vivo differentiation using sagm components
The cells are differentiated from the AT-MSCs by seeding AT-MSCs ex vivo on the substrate and exposing the seeded substrate to small airway growth medium comprising at least one of retinoic acid and human epidermal growth factor.
Overall, the claim set provided defines an AT-MSC-derived epithelial lung cell population dominated by Clara cells while lacking cytokeratin-5 expression, with further confinement to a decellularized lung tissue substrate and specific ECM components. Additional dependent features include the presence of genetically modified cells expressing a therapeutic gene and an ex vivo differentiation using small airway growth medium containing retinoic acid and/or human epidermal growth factor.
Stated Advantages
Documented Applications
Alleviating or treating lung defects or lung diseases by administering differentiated lung cells to a mammal.
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