Methods and compositions for modulating the development of stem cells

• US 20070155661A1
• Filed: 02/17/2004
• Published: 07/05/2007
• Est. Priority Date: 02/14/2003
• Status: Abandoned Application

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Kim, Seung
• Application Number:
  US10/545,582
• Publication Number:
  US 20070155661A1
• Time in Patent Office: Days
• US Class Current: 424/93.100
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: C12N 2501/19 Growth and differentiation factors [GDF]
• CPC Class Codes: C12N 2506/02 from embryonic cells
• CPC Class Codes: C12N 5/0676 Pancreatic cells

Abstract

The application provides, among other things, methods for increasing production of insulin in cells by contacting the cells with a BMP family member and/or an activator of a BMP pathway. The application also provides methods for increasing the production of beta cell precursor cells by contacting suitable cells with an inhibitor of a BMP pathway.

Claims

1. A method for increasing insulin production in a cell composition comprising stem cells, the method comprising contacting the cell composition with a BMP family member.

2. The method of claim 1, wherein the BMP family member is a member of a GDF8/GDF11 subfamily.

4. The method of claim 1, wherein the BMP family member binds to an ActRIIA and/or ActRIIB receptor.

5. The method of claim 4, wherein the BMP family member increases one or more of the following in a stem cell:

(a) Smad2 phosphorylation (b) Smad3 phosphorylation and (c) expression of a gene that is positively regulated by Smad4.

7. The method of claim 1, wherein the cell composition comprises beta cell precursor cells.

36. A method for increasing insulin production in a subject comprising administering to the subject a composition comprising insulin producing cells produced according to the method of any of claims 1, 8, 10 or 23.

3. (canceled)

6. (canceled)

8. A method for promoting the maturation of beta cell precursor cells, the method comprising contacting beta cell precursor cells with a BMP family member.

9. The method of claim 8, wherein the beta cell precursor cells express neuroD, nk×

6.1 and/or nk33 2.2.

10. A method for increasing insulin production in a cell composition comprising stem cells, the method comprising contacting the cell composition with a substance that stimulates an ActRIIA and/or ActRIIB signaling pathway.

11. The method of claim 10, wherein the substance causes an increase in one or more of the following (a) Smad2 function (b) Smad3 function and (c) expression of a gene that is positively regulated by Smad4.

14. The method of claim 10, wherein the substance is a member of the GDF8/GDF11 subfamily.

15. The method of claim 10, wherein the substance is a nucleic acid comprising a nucleic acid sequence encoding a positive regulator of the ActRIIA and/or ActRIIB signaling pathway.

16. The method of claim 10, wherein the positive regulator is selected from the group consisting of:

Smad2, Smad3, Smad4 and a GDF8/GDF11 subfamily member.

17. The method of claim 10, wherein the substance causes the inhibition of an inhibitor of the ActRIIA and/or ActRIIB signaling pathway.

12. (canceled)

13. (canceled)

18. (canceled)

19. A method for promoting the formation of beta cell precursor cells in a cell composition comprising stem cells, the method comprising contacting the cell composition with a substance that inhibits a BMP signaling pathway.

20. The method of claim 19, wherein the substance that inhibits a BMP signaling pathway is a secreted polypeptide that binds directly to a BMP family member.

21. The method of claim 19, wherein the substance that inhibits a BMP signaling pathway is selected from the group consisting of:

a noggin, a chordin and a follistatin.

22. The method of claim 19, wherein the substance that antagonizes a BMP signaling pathway is a nucleic acid comprising a coding sequence for a polypeptide antagonist of a BMP signaling pathway.

37. A method for increasing the number of beta cell precursor cells in a subject comprising administering to the subject a composition comprising beta cell precursor cells produced according to the method of claim 19.

23. A method for culturing a cell composition comprising stem cells to obtain an insulin producing cell composition, the method comprising:

a) culturing the cell composition in the presence of a substance that inhibits a BMP signaling pathway; and

b) culturing cells from (a) in the presence of a substance that stimulates a BMP signaling pathway.

24. The method of claim 23, wherein the substance that inhibits a BMP signaling pathway is a secreted polypeptide that binds directly to a BMP family member.

25. The method of claim 23, wherein the substance that inhibits BMP signaling is selected from the group consisting of:

a noggin and a chordin.

26. The method of claim 23, wherein the substance that stimulates a BMP signaling pathway is a BMP family member.

27. The method of claim 26, wherein the BMP family member is a member of a GDF8/GDF11 subfamily.

29. The method of claim 23, wherein the stem cells are islet precursor cells.

28. (canceled)

30. (canceled)

31. A method for increasing insulin production in a subject, the method comprising administering to the subject a BMP family member in an amount sufficient to increase insulin production.

32. The method of claim 31, wherein the subject has been diagnosed with type I or type II diabetes.

33. The method of claim 31, wherein the BMP family member is a member of a GDF8/GDF11 subfamily.

34. A method for increasing the production of islet precursor cells in a subject, the method comprising administering to the subject a substance that inhibits a BMP signaling pathway.

35. The method of claim 34, wherein the substance that inhibits BMP signaling is selected from the group consisting of:

a noggin, a chordin and a follistatin.

38-46. -46. (canceled)