Stem cells having increased sensitivity to SDF-1 and methods of generating and using same

• US 8,252,588 B2
• Filed: 04/07/2004
• Issued: 08/28/2012
• Est. Priority Date: 04/08/2003
• Status: Expired due to Fees

• Current Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Original Assignee: Yeda Research and Development Co. Ltd. (Weizmann Institute of Science)
• Inventors: Kollet, Orit, Lapidot, Tsvee
• Primary Examiner(s): SHEN, WU CHENG WINSTON
• Application Number:
  US10/552,299
• Publication Number:
  US 20070003540A1
• Time in Patent Office: 3,065 Days
• Field of Search: 435/375, 435/377
• US Class Current: 435/375
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 35/16 Blood plasma; Blood serum umbilical cord blood A61K35/51
• 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 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2501/12 Hepatocyte growth factor [HGF]
• CPC Class Codes: C12N 2501/125 Stem cell factor [SCF], c-kit ligand [KL]
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 2501/70 Enzymes
• CPC Class Codes: C12N 5/0647 Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

The present invention relates to stem cells which exhibit increased sensitivity to a chemoattractant and, more particularly, to methods of generating and using them such as in clinical applications involving stem cell transplantation.

Claims

1. A method of increasing sensitivity of hematopoietic stem cells to a chemoattractant, the method comprising exposing the hematopoietic stem cells in vitro to a matrix metalloprotease or an active portion thereof, thereby increasing the level of CXCR4 on the surface of the hematopoietic stem cells and increasing the sensitivity of the hematopoietic stem cells to the chemoattractant.

2. The method of claim 1, wherein said matrix metalloprotease is selected from the group consisting of MMP-2, MMP-3, MMP-9, MMP-10, MMP-13 and MMP-14.

3. The method of claim 1, wherein said matrix metalloprotease is selected from the group consisting of MMP-2 and MMP-9.

4. The method of claim 1, wherein said hematopoietic stem cells are CD34+ hematopoietic stem cells.

5. The method of claim 4, wherein said hematopoietic stem cells are CD34+/CD38−

/low hematopoietic stem cells.

6. The method of claim 1, wherein said exposing the hematopoietic stem cells to said matrix metalloprotease or said active portion thereof, is effected by:

(i) expressing a polynucleotide encoding said matrix metalloprotease or an active portion thereof in the hematopoietic stem cells;

or

(ii) contacting the hematopoietic stem cells with said matrix metalloprotease or an active portion thereof.

7. A method of generating hematopoietic stem cells suitable for transplantation, the method comprising:

(a) exposing isolated hematopoietic stem cells in vitro to an exogenous matrix metalloprotease or an active portion thereof; and

(b) isolating hematopoietic stem cells having increased CXCR4 levels compared to hematopoietic stem cells not exposed to the matrix metalloprotease or an active portion thereof, to thereby generate hematopoietic stem cells suitable for transplantation.

8. The method of claim 7, wherein said matrix metalloprotease is selected from the group consisting of MMP-2, MMP-3, MMP-9, MMP-10, MMP-13 and MMP-14.

9. The method of claim 7, wherein said matrix metalloprotease is selected from the group consisting of MMP-2 and MMP-9.

10. The method of claim 7, wherein said hematopoietic stem cells are CD34+ hematopoietic stem cells.

11. The method of claim 7, wherein said hematopoietic stem cells are CD34+/CD38−

/low hematopoietic stem cells.

12. The method of claim 7, wherein said exposing said hematopoietic stem cells to said exogenous matrix metalloprotease or said active portion thereof, is effected by:

(i) expressing a polynucleotide encoding said matrix metalloprotease or said active portion thereof in said hematopoietic stem cells;

or

(ii) contacting said hematopoietic stem cells with said matrix metalloprotease or said active portion thereof.

13. The method of claim 7, wherein said isolating hematopoietic stem cells having increased CXCR4 levels compared to hematopoietic stem cells not exposed to the matrix metalloprotease or an active portion thereof is effected by FACS.