Compositions and methods for promoting intestinal stem cell and/or non-stem progenitor cell function
Disclosed herein are novel methods and compositions useful for promoting intestinal stem cell function. The methods and compositions are particularly useful for stimulating the proliferation of and/or self-renewal of intestinal stem cells, as well as for minimizing, preventing, or ameliorating cellular damage resulting from incidental or accidental exposure to radiation (e.g., cancer radiation therapy).
1. A method of stimulating the proliferation and/or self-renewal of one or more intestinal stem cells in mammalian intestinal tissue in a subject, the method comprising contacting a population of cells in the mammalian intestinal tissue with an effective amount of a compound that increases the level and/or activity of peroxisome proliferator activated receptor delta (PPAR-δ) or a PPAR-δ target protein, thereby stimulating the proliferation and/or self-renewal of one or more intestinal stem cells, wherein the contacting of the population of cells with the effective amount of the compound occurs in a subject suffering a disease characterized by intestinal stem cells that require increased proliferation and/or self-renewal, wherein the compound comprises a PPAR-δ agonist or a PPAR-δ target protein agonist selected from the group consisting of a CPT1A agonist, a HMGCS2 agonist, and a FABP1 agonist.
2. A method according to claim 1 wherein the intestinal stem cells comprise leucine-rich repeat-containing G-protein coupled receptor 5-positive (LGR5 + ) stem cells.
3. A method according to claim 1 wherein the compound comprises a PPAR-δ agonist.
4. A method according to claim 1 wherein the compound comprises 2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid (GW501516).
5. A method according to claim 1 wherein the contacting occurs in vivo in a subject.
6. A method according to claim 5 wherein the subject is selected for treatment of a gastrointestinal disorder selected from the group consisting of inflammatory bowel disease, infectious colitis, ischemic colitis, and inflammatory colitis.
7. A method according to claim 5 wherein the subject is selected for treatment of an affliction characterized by intestinal atrophy selected from the group consisting of an inflammatory disease, an autoimmune disease, vascular disease, cancer, infection, short bowel syndrome, drug-induced or toxin-induced intestinal injury, total parenteral nutrition, and exposure to ionizing radiation.
8. A method according to claim 7 wherein exposure to ionizing radiation is from an ionizing radiation source selected from the group consisting of a nuclear power plant, a nuclear weapon, radiotherapy, and space or cosmic radiation.
9. A method according to claim 5 further comprising determining that the subject is in need of enhanced intestinal function.
10. A method of promoting regeneration of mammalian intestinal tissue in a subject, the method comprising contacting a population of cells in the mammalian intestinal tissue with an effective amount of a compound that increases the level and/or activity of peroxisome proliferator activated receptor delta (PPAR-δ) or a PPAR-δ target protein, thereby promoting regeneration of the mammalian intestinal tissue, wherein the contacting of the population of cells with the effective amount of the compound occurs in a subject suffering a disease characterized by mammalian intestinal tissue that requires promoted regeneration, wherein the compound comprises a PPAR-δ agonist or a PPAR-δ target protein agonist selected from the group consisting of a CPT1A agonist, a HMGCS2 agonist, and a FABP1 agonist.
11. A method according to claim 10 wherein the population of cells comprises intestinal stem cells that comprise leucine-rich repeat-containing G-protein coupled receptor 5-positive (LGR5 + ) stem cells.
12. A method according to claim 10 wherein the compound comprises a PPAR-δ agonist.
13. A method according to claim 10 wherein the compound comprises 2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid (GW501516).
14. A method according to claim 10 wherein the contacting occurs in vivo in a subject.
15. A method according to claim 14 wherein the subject is selected for treatment of an affliction characterized by intestinal atrophy selected from the group consisting of an inflammatory disease, an autoimmune disease, vascular disease, cancer, infection, short bowel syndrome, drug-induced or toxin-induced intestinal injury, total parenteral nutrition, and exposure to ionizing radiation.
16. A method of treating an affliction characterized by intestinal atrophy in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition that increases the level and/or activity of PPAR-δ or a PPAR-δ target protein, thereby treating the affliction characterized by intestinal atrophy, wherein the composition comprises a PPAR-δ agonist or a PPAR-δ target protein agonist selected from the group consisting of a CPT1A agonist, a HMGCS2 agonist, and a FABP1 agonist.
17. A method according to claim 16 further comprising determining that the subject is in need of treatment for an affliction characterized by intestinal atrophy.
18. A method according to claim 16 wherein the affliction is selected from the group consisting of an inflammatory disease, an autoimmune disease, vascular disease, cancer, infection, short bowel syndrome, drug-induced or toxin-induced intestinal injury, total parenteral nutrition, and exposure to ionizing radiation.
19. A method according to claim 16 wherein the composition comprises a PPAR-δ agonist and a pharmaceutically acceptable carrier, diluent, or excipient.
20. A method according to claim 19 wherein the PPAR-δ agonist comprises GW501516.
21. A method according to claim 1 wherein the compound comprises a PPAR-δ target protein agonist selected from the group consisting of a CPT1A agonist, a HMGCS2 agonist, and a FABP1 agonist.
22. A method according to claim 3 wherein the PPAR-δ agonist is a compound of formula (I):
wherein X represents a COOH or a hydrolysable ester thereof; X 1 is O or S; X 2 is O or S; R 1 and R 2 independently represent H, CH 3 , OCH 3 , or halogen; n is 1 or 2; one of Y and Z is N and the other is S or O; y is 1 or 2; and each R 3 independently represents CF 3 or halogen.