METHODS OF CELLULAR REPROGRAMMING
Disclosed herein are methods of cellular reprogramming, comprising contacting a cell with HC-HA/PTX3 for a time sufficient for cellular reprogramming of the phenotype of the cell to a different phenotype.
1 . A method of reprogramming a cell having a first phenotype, comprising: contacting the cell with HC-HA/PTX3 for a time sufficient to reprogram the first phenotype of the cell to second phenotype.
2 . The method of claim 1 , wherein the second phenotype corresponds to a phenotype of an earlier cell in a cellular differentiation pathway.
3 . The method of claim 1 , wherein the cell is reprogrammed into an earlier cell in a cellular differentiation pathway.
4 . The method of claim 1 , wherein the cell is a cell differentiated from a progenitor cell.
5 . The method of claim 4 , wherein the progenitor cell is a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
6 . The method of claim 4 , wherein the progenitor cell is a neural crest progenitor.
7 . The method of any one of claims 4 - 6 , wherein the cell differentiated from the progenitor cell is a mesenchymal cell.
8 . The method of claim 4 , wherein the cell differentiated from the progenitor cell is a fibroblast, myofibroblast, keratocyte, epithelial cell, or limbal niche cell.
9 . The method of claim 8 , wherein the fibroblast is a myofibroblast, a dermal fibroblast, a corneal fibroblast, or a cardiac fibroblast.
10 . The method of any one of claims 4 - 9 , wherein the earlier cell is the progenitor cell.
11 . The method of any one of claims 1 - 10 , wherein the cell is present in a tissue following damage or degeneration of the tissue.
12 . The method of claim 11 , wherein the tissue is ocular, cardiac, skin, joint, spine, soft tissue, cartilage, bone, tendon, ligament, nerve, intervertebral disc, spinal cord, brain, or muscle tissue.
13 . The method of claim 11 , wherein the tissue is cardiac tissue.
14 . The method of claim 11 , wherein the tissue is ocular tissue.
15 . The method of any one of claims 11 - 14 , wherein the damage is the result of a burn, a laceration, ischemic tissue, a wound, an injury, an ulcer, radiation, chemotherapy, or a surgical incision.
16 . The method of claim 15 , wherein the injury is a myocardial infarction.
17 . The method of any one of claims 1 - 16 , wherein the HC-HA/PTX3 is comprised in a preparation of a fetal support tissue.
18 . The method of claim 17 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
19 . The method of claim 17 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
20 . The method of claim 17 or claim 19 , wherein the fetal support tissue is frozen or previously frozen.
21 . The method of any one of claims 17 - 20 , wherein the fetal support tissue is substantially free of red blood cells.
22 . The method of any one of claims 17 - 21 , wherein the fetal support tissue comprises umbilical cord substantially free of a vein or artery.
23 . The method of any one of claims 17 - 22 , wherein the fetal support tissue comprises cells, substantially all of which are dead.
24 . The method of any one of claims 17 - 23 , wherein the fetal support tissue comprises umbilical cord amniotic membrane and at least a portion of Wharton's Jelly.
25 . The method of any one of claims 17 - 24 , wherein the fetal support tissue is cryopreserved, lyophilized, sterilized, or a combination thereof.
26 . The method of any of claims 1 - 25 , wherein the composition is a gel, a solution, or a suspension.
27 . The method of any of claims 1 - 26 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.
28 . The method of any one of claims 1 - 27 , further comprising contacting the fibroblastic cell with TGFβ1.
29 . A method of treating a condition characterized by unwanted fibroblastic cell differentiation in a subject in need thereof comprising, contacting a fibroblastic cell within a tissue affected by the condition in the subject with HC-HA/PTX3 for a period of time sufficient to reprogram a phenotype of the fibroblastic cell to a different phenotype, thereby treating the condition.
30 . The method of claim 29 , wherein the different phenotype corresponds to a phenotype of an earlier cell in a cellular differentiation pathway.
31 . The method of claim 29 , wherein the fibroblastic cell is reprogrammed into an earlier cell in a cellular differentiation pathway.
32 . The method of claim 29 , wherein the fibroblastic cell is a cell differentiated from a progenitor cell.
33 . The method of claim 32 , wherein the progenitor cell is a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
34 . The method of claim 32 , wherein the progenitor cell is a neural crest progenitor.
35 . The method of any one of claims 32 - 34 , wherein the cell differentiated from the progenitor cell is a mesenchymal cell.
36 . The method of claim 32 , wherein the cell differentiated from the progenitor cell is a fibroblast, myofibroblast, keratocyte, epithelial cell, or limbal niche cell.
37 . The method of claim 36 , wherein the fibroblast is a myofibroblast, a dermal fibroblast, a corneal fibroblast, or a cardiac fibroblast.
38 . The method of claim 30 or claim 31 , wherein the earlier cell is the progenitor cell.
39 . The method of any one of claims claim 29 - 38 , wherein the tissue is ocular, cardiac, skin, joint, spine, soft tissue, cartilage, bone, tendon, ligament, nerve, intervertebral disc, spinal cord, brain, or muscle tissue.
40 . The method of any one of claims claim 29 - 38 , wherein the tissue is ocular tissue.
41 . The method of any one of claims claim 29 - 38 , wherein the tissue is cardiac tissue.
42 . The method of claim 41 , wherein the condition is myocardial infarction.
43 . The method of claim 42 , wherein the contacting occurs during a stent placement surgical procedure.
44 . The method of any one of claims 29 - 41 , wherein the condition occurs as the result of a burn, a laceration, ischemic tissue, a wound, an injury, an ulcer, radiation, chemotherapy, or a surgical incision.
45 . The method of any one of claims 29 - 44 , wherein HC-HA/PTX3 is comprised in a preparation of fetal support tissue.
46 . The method of claim 44 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
47 . The method of claim 45 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
48 . The method of claim 45 or claim 47 , wherein the fetal support tissue is frozen or previously frozen.
49 . The method of any one of claims 45 - 48 , wherein the fetal support tissue is substantially free of red blood cells.
50 . The method of any one of claims 45 - 49 , wherein the fetal support tissue comprises umbilical cord substantially free of a vein or artery.
51 . The method of any one of claims 45 - 50 , wherein the fetal support tissue comprises cells, substantially all of which are dead.
52 . The method of any one of claims 45 - 51 , wherein the fetal support tissue comprises umbilical cord amniotic membrane and at least a portion of Wharton's Jelly.
53 . The method of any one of claims 45 - 52 , wherein the fetal support tissue is cryopreserved, lyophilized, sterilized, or a combination thereof.
54 . The method of any of claims 29 - 53 , wherein the composition is a gel, a solution, or a suspension.
55 . The method of any of claims 29 - 54 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.
56 . The method of any one of claims 29 - 55 , further comprising contacting the fibroblastic cell with TGFβ1.
57 . A method of reversing a disease state in a tissue comprising, contacting the tissue with HC-HA/PTX3 for a time sufficient to reprogram diseased or unwanted cells in the tissue to a cell having a different phenotype, thereby reversing the disease state of the tissue.
58 . The method of claim 57 , wherein the different phenotype corresponds to a phenotype of an earlier cell in a cellular differentiation pathway.
59 . The method of claim 57 , wherein different phenotype corresponds to a phenotype of a progenitor cell.
60 . The method of claim 59 , wherein the progenitor cell is a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
61 . The method of claim 57 , wherein the unwanted cell is a fibroblast, myofibroblast, keratocyte, epithelial cell, or limbal niche cell.
62 . The method of claim 61 , wherein the fibroblast is a myofibroblast, a dermal fibroblast, a corneal fibroblast, or a cardiac fibroblast.
63 . The method of any one of claims 57 - 62 , wherein the disease or unwanted cell is present in a tissue following scarring, damage, or degeneration of the tissue.
64 . The method of claim 63 , wherein the tissue is ocular, cardiac, skin, joint, spine, soft tissue, cartilage, bone, tendon, ligament, nerve, intervertebral disc, spinal cord, brain, or muscle tissue.
65 . The method of claim 63 , wherein the tissue is cardiac tissue.
66 . The method of claim 63 , wherein the tissue is ocular tissue.
67 . The method of any one of claims 57 - 66 , wherein the HC-HA/PTX3 is comprised in a preparation of a fetal support tissue.
68 . The method of claim 67 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
69 . The method of claim 67 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
70 . The method of any one of claims 67 - 69 , wherein the fetal support tissue comprises cells, substantially all of which are dead.
71 . The method of any one of claims 67 - 70 , wherein the fetal support tissue comprises umbilical cord amniotic membrane and at least a portion of Wharton's Jelly.
72 . The method of any one of claims 67 - 71 , wherein the fetal support tissue is cryopreserved, lyophilized, sterilized, or a combination thereof.
73 . The method of any of claims 57 - 72 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.
74 . A method of producing a progenitor cell from a differentiated cell comprising, contacting the differentiated cell with HC-HA/PTX3 for a time sufficient to reprogram the differentiated cell to a progenitor cell phenotype.
75 . The method of claim 74 , wherein the progenitor cell phenotype corresponds to a phenotype of an earlier cell in a cellular differentiation pathway.
76 . The method of claim 74 , wherein the progenitor cell phenotype corresponds the that of a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
77 . The method of claim 74 , wherein the differentiated cell is a fibroblast, myofibroblast, keratocyte, epithelial cell, or limbal niche cell.
78 . The method of claim 77 , wherein the fibroblast is a myofibroblast, a dermal fibroblast, a corneal fibroblast, or a cardiac fibroblast.
79 . The method of any one of claims 74 - 77 , wherein the differentiated cell is present in a tissue following scarring, damage, or degeneration of the tissue.
80 . The method of claim 79 , wherein the tissue is ocular, cardiac, skin, joint, spine, soft tissue, cartilage, bone, tendon, ligament, nerve, intervertebral disc, spinal cord, brain, or muscle tissue.
81 . The method of claim 79 , wherein the tissue is cardiac tissue.
82 . The method of claim 79 , wherein the tissue is ocular tissue.
83 . The method of any one of claims 74 - 82 , wherein the HC-HA/PTX3 is comprised in a preparation of a fetal support tissue.
84 . The method of claim 83 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
85 . The method of claim 83 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
86 . The method of any one of claims 83 - 85 , wherein the fetal support tissue comprises cells, substantially all of which are dead.
87 . The method of any one of claims 83 - 86 , wherein the fetal support tissue comprises umbilical cord amniotic membrane and at least a portion of Wharton's Jelly.
88 . The method of any one of claims 83 - 87 , wherein the fetal support tissue is cryopreserved, lyophilized, sterilized, or a combination thereof.
89 . The method of any of claims 74 - 88 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.
90 . A method of regenerating a tissue comprising, reprogramming a first differentiated phenotype of a cell within a tissue to a progenitor phenotype, and differentiating the progenitor phenotype into a second differentiated phenotype, thereby regenerating the tissue.
91 . The method of claim 90 , wherein the progenitor cell phenotype corresponds to a phenotype of an earlier cell in a cellular differentiation pathway.
92 . The method of claim 90 , wherein the progenitor cell phenotype corresponds the that of a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
93 . The method of claim 90 , wherein the first differentiated cell is a fibroblast, myofibroblast, keratocyte, epithelial cell, or limbal niche cell.
94 . The method of claim 93 , wherein the fibroblast is a myofibroblast, a dermal fibroblast, a corneal fibroblast, or a cardiac fibroblast.
95 . The method of any one of claims 93 - 94 , wherein the first differentiated cell is present in the tissue following scarring, damage, or degeneration of the tissue.
96 . The method of any one of claims 90 - 95 , wherein the tissue is ocular, cardiac, skin, joint, spine, soft tissue, cartilage, bone, tendon, ligament, nerve, intervertebral disc, spinal cord, brain, or muscle tissue.
97 . The method of any one of claims 90 - 95 , wherein the tissue is cardiac tissue.
98 . The method of any one of claims 90 - 95 , wherein the tissue is ocular tissue.
99 . The method of any one of claims 90 - 98 , wherein the HC-HA/PTX3 is comprised in a preparation of a fetal support tissue.
100 . The method of claim 99 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
101 . The method of claim 99 or claim 100 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
102 . The method of any one of claims 99 - 101 , wherein the fetal support tissue comprises cells, substantially all of which are dead.
103 . The method of any one of claims 99 - 102 , wherein the fetal support tissue comprises umbilical cord amniotic membrane and at least a portion of Wharton's Jelly.
104 . The method of any one of claims 99 - 103 , wherein the fetal support tissue is cryopreserved, lyophilized, sterilized, or a combination thereof.
105 . The method of any of claims 90 - 104 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.
106 . A composition comprising a) HC-HA/PTX3 and b) a therapeutic cell.
107 . The composition of claim 106 , wherein the therapeutic cell is a progenitor cell, a stem cells, or an induced pluripotent stem cell.
108 . The composition of claim 107 , wherein the progenitor cell is a neural crest progenitor, a hematopoietic progenitor cell, a mammary progenitor cell, an intestinal progenitor cell, a mesenchymal progenitor cell, an endothelial progenitor cell, a neural progenitor cell, an olfactory progenitor cell, a testicular progenitor cell, or a cardiovascular progenitor cell.
109 . The composition of any one of claims 106 - 108 , wherein HC-HA/PTX3 is comprised in a preparation of fetal support tissue.
110 . The composition of claim 109 , wherein the preparation is an extract of fetal support tissue, a fetal support tissue homogenate, a fetal support tissue powder, morselized fetal support tissue, pulverized fetal support tissue, ground fetal support tissue, a fetal support tissue graft, purified HC-HA/PTX3, reconstituted HC-HA/PTX3 or a combination thereof.
111 . The composition of claim 109 or claim 110 , wherein the fetal support tissue is selected from placenta, placental amniotic membrane, umbilical cord, umbilical cord amniotic membrane, chorion, amnion-chorion, amniotic stroma, amniotic jelly, or a combination thereof.
112 . The composition of any one of claims 106 - 111 , wherein the HC-HA/PTX3 is native HC-HA/PTX3, reconstituted HC-HA/PTX3, or a combination thereof.