Ex vivo progenitor and stem cell expansion for use in the treatment of disease of endodermally-derived organs
First Claim
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1. A method of enhancing function of an endodermally derived organ in a subject in need thereof, the method comprising:
- (a) obtaining a population of cells comprising stem and/or progenitor cells;
(b) culturing said stem and/or progenitor cells ex-vivo under conditions allowing for cell proliferation and, at the same time, culturing said cells under conditions selected from the group consisting of;
(i) conditions reducing expression and/or activity of CD38 in said cells;
(ii) conditions reducing capacity of said cells in responding to signaling pathways involving CD38 in said cells;
(iii) conditions reducing capacity of said cells in responding to retinoic acid, retinoids and/or Vitamin D in said cells;
(iv) conditions reducing capacity of said cells in responding to signaling pathways involving the retinoic acid receptor, the retinoid X receptor and/or the Vitamin D receptor in said cells;
(v) conditions reducing capacity of said cells in responding to signaling pathways involving PI 3-kinase;
(vi) conditions wherein said cells are cultured in the presence of nicotinamide, a nicotinamide analog, a nicotinamide or a nicotinamide analog derivative or a nicotinamide or a nicotinamide analog metabolite;
(vii) conditions wherein said cells are cultured in the presence of a copper chelator;
(viii) conditions wherein said cells are cultured in the presence of a copper chelate;
(ix) conditions wherein said cells are cultured in the presence of a PI 3-kinase inhibitor;
thereby expanding the stem and/or progenitor cells while at the same time, substantially inhibiting differentiation of the stem and/or progenitor cells ex-vivo; and
(c) implanting said cells in an endodermally-derived organ of the subject.
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Abstract
Methods of ex-vivo expansion of endodermally-derived and non-endodermally-derived progenitor and stem cells, expanded populations of renewable progenitor and stem cells and to their uses in therapeutic applications such as the production of endocrine hormones and the prevention and treatment of liver and pancreatic disease.
132 Citations
52 Claims
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1. A method of enhancing function of an endodermally derived organ in a subject in need thereof, the method comprising:
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(a) obtaining a population of cells comprising stem and/or progenitor cells;
(b) culturing said stem and/or progenitor cells ex-vivo under conditions allowing for cell proliferation and, at the same time, culturing said cells under conditions selected from the group consisting of;
(i) conditions reducing expression and/or activity of CD38 in said cells;
(ii) conditions reducing capacity of said cells in responding to signaling pathways involving CD38 in said cells;
(iii) conditions reducing capacity of said cells in responding to retinoic acid, retinoids and/or Vitamin D in said cells;
(iv) conditions reducing capacity of said cells in responding to signaling pathways involving the retinoic acid receptor, the retinoid X receptor and/or the Vitamin D receptor in said cells;
(v) conditions reducing capacity of said cells in responding to signaling pathways involving PI 3-kinase;
(vi) conditions wherein said cells are cultured in the presence of nicotinamide, a nicotinamide analog, a nicotinamide or a nicotinamide analog derivative or a nicotinamide or a nicotinamide analog metabolite;
(vii) conditions wherein said cells are cultured in the presence of a copper chelator;
(viii) conditions wherein said cells are cultured in the presence of a copper chelate;
(ix) conditions wherein said cells are cultured in the presence of a PI 3-kinase inhibitor;
thereby expanding the stem and/or progenitor cells while at the same time, substantially inhibiting differentiation of the stem and/or progenitor cells ex-vivo; and
(c) implanting said cells in an endodermally-derived organ of the subject. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 50, 51, 52)
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24. A method of expanding and transdifferentiating a population of non-endodermally derived stem cells into stem cells having an endodermal cell phenotype, the method comprising:
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(a) obtaining a population of cells comprising stem and/or progenitor cells;
(b) culturing said stem and/or progenitor cells ex-vivo under conditions allowing for cell proliferation and, at the same time, culturing said cells under conditions selected from the group consisting of;
(i) conditions reducing expression and/or activity of CD38 in said cells;
(ii) conditions reducing capacity of said cells in responding to signaling pathways involving CD38 in said cells;
(iii) conditions reducing capacity of said cells in responding to retinoic acid, retinoids and/or Vitamin D in said cells;
(iv) conditions reducing capacity of said cells in responding to signaling pathways involving the retinoic acid receptor, the retinoid X receptor and/or the Vitamin D receptor in said cells;
(v) conditions reducing capacity of said cells in responding to signaling pathways involving PI 3-kinase;
(vi) conditions wherein said cells are cultured in the presence of nicotinamide, a nicotinamide analog, a nicotinamide or a nicotinamide analog derivative or a nicotinamide or a nicotinamide analog metabolite;
(vii) conditions wherein said cells are cultured in the presence of a copper chelator;
(viii) conditions wherein said cells are cultured in the presence of a copper chelate;
(ix) conditions wherein said cells are cultured in the presence of a PI 3-kinase inhibitor;
thereby expanding the stem and/or progenitor cells while at the same time, substantially inhibiting differentiation of the stem and/or progenitor cells ex-vivo; and
(c) inducing enrichment of said stem/progenitor cells for stem cells expressing endodermal cell markers, thereby expanding and transdifferentiating a population of non-endodermal stem cells into stem cells having an endodermal cell phenotype. - View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49)
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Specification