Methods and compositions for modulating angiogenesis and vasculogenesis
Inventors
Dao, Monique • Tate, Ciara • Case, Casey C.
Assignees
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Publication Number
US-11304982-B2
Publication Date
2022-04-19
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 describes compositions and methods for modulating angiogenesis and vasculogenesis using SB623 cells, which are descendants of marrow-derived mesenchymal stem cells transfected with a polynucleotide encoding the Notch intracellular domain (NICD) but not full-length Notch. The disclosed approach emphasizes administering SB623 cells, optionally together with a pro-angiogenic agent such as VEGF-related nucleic acids/polypeptides or transcription factors.
In vitro and ex vivo results are provided showing that SB623 cell-conditioned medium promotes endothelial cell survival, endothelial cell proliferation, and endothelial tube formation. The disclosure reports reduced PI+ death and increased Bcl-2, increased Ki67, and HUVEC tubulogenesis, together with aortic ring sprouting and branching.
The disclosure further connects these effects to VEGF signaling by reporting that VEGFR2 inhibition with SU5416 partially or fully reduces SB623-conditioned-medium effects. This is used to support an involvement of VEGF in the angiogenesis/vasculogenesis modulation produced by SB623 cells and their conditioned medium.
Claims Coverage
The document includes one independent claim directed to making a composition, with the main inventive features centering on engineering MSCs with an NICD-encoding polynucleotide, selecting engineered cells, and further culturing them in the absence of selection and trophic factors to obtain a composition comprising angiogenin, ANG-2, and HB-EGF.
Engineering MSCs with an NICD-encoding polynucleotide that does not encode full-length Notch
A method that includes contacting a culture of mesenchymal stem cells with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein the polynucleotide does not encode a full-length Notch protein.
Selecting cells comprising the NICD polynucleotide
The method further includes selecting cells that comprise the polynucleotide introduced to the MSC culture.
Culturing selected cells without selection and without trophic factors to obtain a composition comprising angiogenin, ANG-2, and HB-EGF
The method includes further culturing the selected cells in the absence of selection and in the absence of trophic factors, thereby making a composition comprising angiogenin, angiopoietin-2 (ANG-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF).
Overall, claim coverage focuses on NICD-driven engineering of mesenchymal stem cells, followed by selecting engineered cells and culturing them in the absence of selection and trophic factors to produce a composition characterized by named pro-angiogenic factors, with further refinements in dependent claims.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of ischemic disorders, particularly stroke and other central nervous system ischemia.
Repairing ischemic damage, including representative ischemia types such as cerebral ischemia, cardiac ischemia, bowel ischemia, limb ischemia, cutaneous ischemia, ocular ischemia, and cerebral palsy.
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