Perivascular mesenchymal precursor cell induced blood vessel formation

• US 9,169,466 B2
• Filed: 03/29/2004
• Issued: 10/27/2015
• 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:
  US10/551,326
• Publication Number:
  US 20060286077A1
• Time in Patent Office: 4,229 Days
• 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 inducing formation or repair of blood vessels in an ischemic first tissue, comprising contacting the ischemic first tissue with 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 but are negative for CD34, CD45, and glycophorin A, so as to thereby induce formation of blood vessels or repair of existing blood vessels in the ischemic first tissue.

2. The method of claim 1 wherein the population of cells comprises at least 0.01% MPCs capable of forming a clonogenic colony.

3. The method of claim 1 wherein the population of cells comprises at least 0.1% MPCs capable of forming a clonogenic colony.

4. The method of claim 1 wherein the population of cells comprises at least 0.01% STRO-1^bright MPCs.

5. The method of claim 1 wherein the population of cells comprises at least 0.1% STRO-1^bright MPCs.

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

7. The method of claim 1 wherein the MPCs that express the marker STRO-1 additionally co-express the marker VCAM-1.

8. The method of claim 1 wherein the population of cells is derived from a second tissue selected from the group consisting of skin, liver, kidney, heart, adipose tissue, teeth, dental pulp, retina, brain, hair follicles, intestine, lung, spleen, lymph node, thymus, pancreas, bone, ligament, bone marrow, tendon, and skeletal muscle.

9. The method of claim 1 wherein the population of cells is isolated from a perivascular niche within a vascularised tissue source.

10. The method of claim 1 wherein the population of cells is isolated from a perivascular niche within a non-haemopoietic vascularised tissue.

11. The method of claim 1 wherein the population of cells comprises at least 10% STRO-1^bright MPCs.

12. The method claim 1 wherein the MPCs that express the marker STRO-1 co-express any one or more of the markers selected from the group consisting of THY-1, VCAM-1, ICAM-1, PECAM-1, CD49a/CD49b/CD29, CD49c/CD29, CD49d/CD29, CD29, CD61, integrin beta5, 6-19, thrombomodulin, CD10, CD13, SCF, PDGF-R, EGF-R, IGF-1R, NGF-R, FGF-R and Leptin-R (STRO-2).

14. The method according to claim 12, wherein the target tissue is cardiac tissue.

15. The method of claim 1, wherein the ischemic tissue is in a subject suffering from cerebrovascular ischemia, renal ischemia, pulmonary ischemia, limb ischemia, ischemic cardiomyopathy, or myocardial ischemia.

16. The method of claim 1, wherein the MPCs that express the marker STRO-1 are human.

17. The method of claim 1, further comprising seeding the purified populations of human cells in a matrix prior to contacting the first tissue.

18. The method of claim 17, wherein the matrix is a scaffold.

19. The method of claim 18, wherein the scaffold induces differentiation of the population of human cells.

20. The method of claim 1, further comprising contacting the ischemic first tissue with a compound known to promote formation or repair of blood vessels.

35. The method of claim 1, wherein the enriched population is cultured and/or expanded prior to contacting the ischemic first tissue.

13. A method of inducing neovascularisation in a target ischemic tissue of a patient, the method comprising the step of administering to the target ischemic tissue an effective amount of a population of human mesenchymal precursor cells (MPCs) which has been enriched for cells that express the markers STRO-1, CD146, and alpha smooth muscle actin but are negative for CD34, CD45, and glycophorin A.

21. The method of claim 13, wherein the population of cells comprises at least 0.01% MPCs capable of forming a clonogenic colony.

22. The method of claim 13, wherein the population of cells comprises at least 0.1% MPCs capable of forming a clonogenic colony.

23. The method of claim 21, wherein the population of cells comprises at least 0.01% STRO-1^bright MPCs.

24. The method of claim 22, wherein the population of cells comprises at least 0.1% STRO-1^bright MPCs.

25. The method of claim 13, wherein the population of cells comprises at least 1% STRO-1^bright MPCs.

26. The method of claim 25, wherein the MPCs that express the marker STRO-1 additionally co-express the marker VCAM-1.

27. The method of claim 25, wherein the population of cells is derived from a second tissue of the patient selected from the group consisting of skin, liver, kidney, heart, adipose tissue, teeth, dental pulp, retina, brain, hair follicles, intestine, lung, spleen, lymph node, thymus, pancreas, bone, ligament, tendon, and skeletal muscle.

28. The method of claim 25, wherein the population of cells is isolated from a perivascular niche within a vascularised tissue source.

29. The method of claim 25, wherein the population of cells is isolated from a perivascular niche within a non-haemopoietic vascularised tissue.

30. The method of claim 25, further comprising seeding the population of human cells in a matrix prior to contacting the first tissue.

31. The method of claim 30, wherein the matrix is a scaffold.

32. The method of claim 31, wherein the scaffold induces differentiation of the population of human cells.

33. The method of claim 25, further comprising administering to the patient a compound known to promote formation or repair of blood vessels.

34. The method of claim 33, wherein the population of human MPCs and the compound known to promote formation or repair of blood vessels are coadministered.

36. The method of claim 13, wherein the enriched population is cultured and/or expanded prior to contacting the ischemic first tissue.