Methods and compositions for modulating angiogenesis and vasculogenesis
Inventors
Dao, Monique • Tate, Ciara • Case, Casey C.
Assignees
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Publication Number
US-12171787-B2
Publication Date
2024-12-24
Expiration Date
Abstract
Disclosed herein are methods and compositions for stimulating angiogenesis, using cells descended from marrow adherent stromal cells that have been transfected with sequences encoding a Notch intracellular domain. Applications of these methods and compositions include treatment of ischemic disorders such as stroke.
Core Innovation
The disclosure relates to a cell population produced from mesenchymal stem cells that are contacted with a polynucleotide encoding a Notch intracellular domain (NICD) in which the polynucleotide does not encode a full-length Notch protein. Cells comprising the polynucleotide are selected and further cultured in the absence of selection and in the absence of trophic factors. The resulting cell population is characterized as producing higher levels of angiogenin, angiopoietin-2 (ANG-2), and HB-EGF than a mesenchymal stem cell population containing the same number of cells.
The disclosure further describes that the higher production of angiogenin, angiopoietin-2 (ANG-2), and HB-EGF by the cell population is associated with augmenting angiogenesis. In examples described in the document, endothelial-cell outcomes include endothelial survival, endothelial proliferation, tube formation, vessel sprouting, and vessel branching in central nervous system and brain contexts. VEGFR2 signaling inhibition is described as partially reducing viability/proliferation effects and fully reversing tube-formation stimulation by SB623-conditioned medium, supporting VEGF’s major role alongside additional factors.
In addition, the disclosure describes that conditioned medium from SB623 cells shows increased angiogenin, angiopoietin-2 (ANG-2), and HB-EGF compared with MSC controls, with VEGF prominently elevated. The document also describes therapeutic compositions and kits, including optional combination with pro-angiogenic agents such as VEGF pathway activators.
Claims Coverage
The independent claim set is directed to augmenting angiogenesis by implanting an engineered mesenchymal stem cell population characterized by expression of a Notch intracellular domain (NICD) without full-length Notch, and by producing higher levels of specific angiogenic factors (angiogenin, ANG-2, and HB-EGF). The coverage centers on inventive features relating to the engineered cell population and its angiogenic factor output, while dependent claims refine the subject and angiogenic mechanisms and enumerate additional growth factors/proteins produced by the engineered cells.
Augmenting angiogenesis by implanting NICD-expressing MSC-derived cells without full-length Notch
A method for augmenting angiogenesis in a subject that does not have an ischemic disorder by implanting a population of cells, where the cell population is made by contacting mesenchymal stem cells with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein said polynucleotide does not encode a full-length Notch protein, selecting cells that comprise the polynucleotide, and further culturing the selected cells in the absence of selection and in the absence of trophic factors.
Increasing angiogenin, angiopoietin-2, and HB-EGF relative to equal-number MSC controls
The method where the cell population produces higher levels of angiogenin, angiopoietin-2 (ANG-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) than does a mesenchymal stem cell population containing the same number of cells.
Overall, the claims cover an angiogenesis-augmenting method that depends on implanting a NICD-only (not full-length Notch) polynucleotide-engineered mesenchymal stem cell-derived population that is characterized by producing higher levels of angiogenin, ANG-2, and HB-EGF relative to an equal-number MSC control population. Dependent claims further narrow the subject and the angiogenesis mechanism (including endothelial survival and prevention of endothelial cell death, and vessel sprouting) and expand the list of proteins/growth factors produced by the engineered cells.
Stated Advantages
Produces higher levels of angiogenin, angiopoietin-2 (ANG-2) and HB-EGF than a mesenchymal stem cell population containing the same number of cells.
Documented Applications
Augmenting angiogenesis in a subject that does not have an ischemic disorder.
Treatment-focused context for ischemic disorders is described, including stroke, in central nervous system/brain contexts.
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