Lineage-directed induction of human mesenchymal stem cell differentiation

• US 5,942,225 A
• Filed: 07/23/1997
• Issued: 08/24/1999
• Est. Priority Date: 01/24/1995
• Status: Expired due to Term

• Current Assignee: Case Western Reserve University, Osiris Therapeutics Incorporated (Smith & Nephew PLC)
• Original Assignee: Case Western Reserve University, Osiris Therapeutics Incorporated (Smith & Nephew PLC)
• Inventors: Caplan, Arnold I., Bruder, Scott P., Haynesworth, Stephen E.
• Primary Examiner(s): Lankford, Jr., Leon B.
• Application Number:
  US08/899,414
• Time in Patent Office: 762 Days
• Field of Search: 424/93.7, 435/366, 435/372
• US Class Current: 424/93.7
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 38/2006 IL-1
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C12N 2500/42 Organic phosphate, e.g. beta glycerophosphate
• CPC Class Codes: C12N 2501/06 Anti-neoplasic drugs, anti-retroviral drugs, e.g. azacytidine, cyclophosphamide
• CPC Class Codes: C12N 2501/155 Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
• CPC Class Codes: C12N 2501/2301 Interleukin-1 (IL-1)
• CPC Class Codes: C12N 2501/39 : Steroid hormones
• CPC Class Codes: C12N 5/0654 : Osteocytes, Osteoblasts, Odontocytes; Bones, Teeth
• CPC Class Codes: C12N 5/0655 : Chondrocytes; Cartilage
• CPC Class Codes: C12N 5/0658 : Skeletal muscle cells, e.g. myocytes, myotubes, myoblasts
• CPC Class Codes: C12N 5/0663 : Bone marrow mesenchymal stem cells (BM-MSC)

Abstract

Methods for in vitro or ex vivo lineage directed induction of isolated, culture expanded human mesenchymal stem cells comprising contacting the mesenchymal stem cells with a bioactive factor effective to induce differentiation thereof into a lineage of choice as well as such compositions including isolated culture expanded human mesenchymal stem cells and bioactive factors effective to induce directed lineage induction are disclosed. Further disclosed is this method which also includes introducing such culturally expanded lineage-induced mesenchymal stem cells into a host from which they have originated for purposes of mesenchymal tissue regeneration or repair.

Claims

1. A composition for inducing lineage-directed differentiation of isolated human mesenchymal stem cells into a single particular mesenchymal lineage, which comprises human mesenchymal stem cells and one or more bioactive factors for inducing differentiation of the mesenchymal stem cells into a single particular lineage.

2. The composition of claim 1 wherein the composition comprises a mixture of bioactive factors.

3. The composition of claim 1 wherein the bioactive factor induces differentiation of isolated human mesenchymal stem cells into a mesenchymal lineage selected from the group consisting of osteogenic, chondrogenic, tendonogenic, ligamentogenic, myogenic, marrow stromagenic, adipogenic and dermogenic.

4. The composition of claim 1 further comprising a pharmaceutically acceptable carrier.

5. The composition of claim 4 wherein the carrier is an injectable liquid.

6. The composition of claim 4 wherein the carrier is a rigid porous vessel.

7. The composition of claim 4 wherein the carrier is a gel.

8. The composition of claim 1 wherein the bioactive factor is an osteoinductive factor for inducing osteogenic lineage differentiation of the human mesenchymal stem cells.

9. The composition of claim 8 wherein the osteoinductive factor is a bone morphogenic protein.

10. The composition of claim 9 wherein the bone morphogenic protein is selected from the group consisting of BMP-2 and BMP-3.

11. The composition of claim 8 wherein the osteoinductive factor is a fibroblast growth factor.

12. The composition of claim 11 wherein the fibroblast growth factor is basic fibroblast growth factor.

13. The composition of claim 8 wherein the osteoinductive factor is a glucocorticoid.

14. The composition of claim 13 wherein the glucocorticoid is dexamethasone.

15. The composition of claim 8 wherein the osteoinductive factor is a prostaglandin.

16. The composition of claim 15 wherein the prostaglandin is prostaglandin E1.

17. The composition of claim 8 which further comprises contacting the isolated human mesenchymal stem cells with an adjunct factor.

18. The composition of claim 17 wherein the adjunct factor is selected from the group consisting of ascorbic acid and its analogs and a glycerophosphate.

19. The composition of claim 1 wherein the bioactive factor is a chondroinductive factor for inducing chondrogenic lineage differentiation of the human mesenchymal stem cells.

20. The composition of claim 19 wherein the chondroinductive factor is a member of the transforming growth factor-β

superfamily.

21. The composition of claim 20 wherein the transforming growth factor-β

superfamily member is TGF-β

1.

22. The composition of claim 20 wherein the transforming growth factor-β

superfamily member is inhibin A.

23. The composition of claim 20 wherein the transforming growth factor-β

superfamily member is chondrogenic stimulating activity factor.

24. The composition of claim 20 wherein the transforming growth factor-β

superfamily member is a bone morphogenic protein.

25. The composition of claim 24 wherein the bone morphogenic protein is BMP-4.

26. The composition of claim 19 wherein the chondroinductive factor is a component of the collagenous extracellular matrix.

27. The composition of claim 26 wherein the collagenous extracellular matrix component is collagen I.

28. The composition of claim 27 wherein the collagen I is in the form of a gel.

29. The composition of claim 19 wherein the chondroinductive factor is a vitamin A analog.

30. The composition of claim 29 wherein the vitamin A analog is retinoic acid.

31. The composition of claim 1 wherein the bioactive factor is a stromainductive factor for inducing stromagenic lineage differentiation of the human mesenchymal stem cells.

32. The composition of claim 31 wherein the stromainductive factor is an interleukin.

33. The composition of claim 32 wherein the interleukin is selected from the group consisting of interleukin-1α

and interleukin-2.

34. The composition of claim 1 wherein the bioactive factor is a myoinductive factor for inducing myogenic lineage differentiation of the human mesenchymal stem cells.

35. The composition of claim 34 wherein the myoinductive factor is a cytidine analog.

36. The composition of claim 35 wherein the cytidine analog is selected from the group consisting of 5-azacytidine and 5-aza-2'"'"'-deoxycytidine.