Perivascular mesenchymal precursor cell induced blood vessel formation

• US 9,175,267 B2
• Filed: 01/05/2006
• Issued: 11/03/2015
• Est. Priority Date: 03/28/2003
• Status: Active Grant

• Current Assignee: Mesoblast, Inc. (Mesoblast Ltd.)
• Original Assignee: Mesoblast, Inc. (Mesoblast Ltd.)
• Inventors: Gronthos, Stan, Zannettino, Andrew
• Primary Examiner(s): Babic, Christopher M
• Assistant Examiner(s): Hiriyanna, Kelaginamane T
• Application Number:
  US11/326,736
• Publication Number:
  US 20060193840A1
• Time in Patent Office: 3,589 Days
• Field of Search: 424/93.1
• US Class Current: 1/1
• 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 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/44 Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 2500/42 Organic phosphate, e.g. beta glycerophosphate
• CPC Class Codes: C12N 2501/11 Epidermal growth factor [EGF]
• CPC Class Codes: C12N 2501/135 Platelet-derived growth factor [PDGF]
• CPC Class Codes: C12N 2501/165 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: C12N 2501/235 Leukemia inhibitory factor [LIF]
• CPC Class Codes: C12N 2501/39 Steroid hormones
• CPC Class Codes: C12N 2506/1392 from mesenchymal stem cells from other natural sources
• CPC Class Codes: C12N 5/0663 Bone marrow mesenchymal stem cells (BM-MSC)
• CPC Class Codes: C12N 5/0667 Adipose-derived stem cells [ADSC]; Adipose stromal stem cells
• CPC Class Codes: C12N 5/0668 Mesenchymal stem cells from other natural sources
• CPC Class Codes: C12N 5/0691 Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels

Abstract

Mesenchymal precursors cells have been isolated from perivascular niches from a range of tissues utilizing a perivascular marker. A new mesenchymal precursor cell phenotype is described characterized by the presence of the perivascular marker 3G5, and preferably also alpha smooth muscle actin together with early developmental markers such as STRO-1 and CD146/MUC18. The perivascular mesenchymal precursor cell is shown to induce neovascularization and improvement in cardiac function. Suitable administration of preparations of the mesenchymal precursor cells are useful for treatment of cardiovascular diseases, cerebrovascular diseases and peripheral vascular diseases.

Claims

1. A method of improving cardiac function in a subject suffering from a cardiovascular disease, the method comprising administering to the myocardium or coronary arteries of the subject a population of cells which has been enriched for mesenchymal precursor cells (MPCs) that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A.

2. The method of claim 1, wherein the subject suffers from a cardiovascular disease consisting of ischemic heart disease, coronary artery disease, acute myocardial infarction, congestive heart failure, cardiomyopathy, or angina.

3. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 1% MPCs capable of forming a clonogenic colony.

4. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 1% STRO-1^bright MPCs.

5. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A is isolated from a perivascular niche within a vascularised tissue source.

6. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A is cultured or expanded prior to administration.

7. The method of claim 6, wherein the cultured or expanded population of cells comprises at least 1% MPCs capable of forming a clonogenic colony.

8. The method of claim 6, wherein the cultured or expanded population of cells comprises at least 1% STRO-1^bright MPCs.

9. The method of claim 6, wherein the cultured or expanded population of cells comprises at least 10% STRO-1^bright MPCs.

10. The method of claim 6, wherein the cultured or expanded population of cells is administered by injection into the myocardium or close to the myocardium.

11. The method of claim 6, wherein the cultured or expanded population of cells is administered by injection into the coronary arteries or close to the coronary arteries.

12. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A is introduced into the body of the subject by localized injection or on a stent.

13. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A is administered by intracoronary catheter, or by intramyocardial, trans-epicardial or transendocardial injection.

14. The method of claim 1, wherein the MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A assemble into new blood vessel structures.

15. The method of claim 1, wherein the MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A induce formation of new blood vessel structures.

16. The method of claim 1, wherein the MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A induce formation of new cardiomyocytes.

17. The method of claim 1, wherein the MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A induce proliferation of resident cardiomyocytes.

18. The method of claim 6, wherein the cultured or expanded population of cells is introduced into the body of the subject by localized injection, systemic injection, in a patch, or on a stent.

19. The method of claim 6, wherein the cultured or expanded population of cells is administered by intracoronary catheter, or by intramyocardial, trans-epicardial or transendocardial injection.

20. The method of claim 6, wherein cells of the cultured or expanded population of cells assemble into new blood vessel structures.

21. The method of claim 6, wherein the cultured or expanded population of cells induces formation of new blood vessel structures.

22. The method of claim 6, wherein the cultured or expanded MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A induce formation of new cardiomyocytes.

23. The method of claim 6, wherein the cultured or expanded MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A induce proliferation of resident cardiomyocytes.

24. The method of claim 1, wherein the cells are autologous.

25. The method of claim 1, wherein the cells are from an allogeneic source.

26. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 0.01% MPCs capable of forming a clonogenic colony.

27. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 0.1% MPCs capable of forming a clonogenic colony.

28. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 0.01% STRO-1^bright MPCs.

29. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 0.1% STRO-1^bright MPCs.

30. The method of claim 1, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A comprises at least 10% STRO-1^bright MPCs.

31. The method of claim 1, further comprising seeding the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A in a matrix prior to administration.

32. The method of claim 31, wherein the matrix is a scaffold.

33. The method of claim 32, wherein the scaffold induces differentiation of the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A.

34. The method of claim 1, further comprising administering to the subject a compound known to promote formation or repair of blood vessels.

35. The method of claim 34, wherein the population of cells which has been enriched for MPCs that express the markers STRO-1, CD146, and alpha-smooth muscle actin and do not express CD34, CD45, and glycophorin-A and the compound known to promote formation or repair of blood vessels are coadministered.