Mobilization of hematopoietic cells
Improved methods and pharmaceutical compositions are provided herein for mobilizing hematopoietic progenitor cells from bone marrow into peripheral blood, comprising the administration of an effective amount of an inhibitor of GTPases, such as Rac1 and Rac2 alone or in combination. Specifically, methods are disclosed for mobilizing hematopoietic stem cells into a subject's peripheral blood. In particular, embodiments of the method involve inhibition of both Rac1 and Rac2 GTPases to increase the numbers of hematopoietic stem cells into a subject's peripheral blood of a subject. The subject's blood can be processed and used to repopulate the destroyed lymphohematopoietic system of a recipient and may in the future be utilized to repair a variety of non-hematopoietic tissues. Therefore, hematopoietic stem cells mobilized into a subject's peripheral blood by the method of the invention is useful as a source of donor cells in bone marrow transplantation for the treatment of a variety of disorders, including cancer, anemia, autoimmunity and immunodeficiency. They can also be used for increasing white blood cell survival and for chemotherapy.
1. A method for mobilizing peripheral blood precursor cells from bone marrow into peripheral blood comprising: administering to a subject in need of treatment to mobilize peripheral blood precursor cells, an effective amount of at least one GTPase inhibitor.
2. The method of claim 1 , wherein the peripheral blood precursor cells are hematopoietic cells selected from the group consisting of progenitor cells and stem cells.
3. The method of claim 1 , wherein said GTPase inhibitor is a Rac GTPase inhibitor.
4. The method of claim 3 , wherein said Rac GTPase inhibitor is an inhibitor of Rac1.
5. The method of claim 4 , further comprising administering an inhibitor of Rac1 and an inhibitor of Rac2.
6. The method of claim 1 , further comprising observing an increased mobility of peripheral blood precursor cells in the subject.
7. The method of claim 6 , wherein said observing comprises collecting a blood sample and counting the number of peripheral blood precursor cells.
8. The method of claim 1 , further comprising collecting mobilized stem cells for identification and/or analysis.
9. The method of claim 1 , further comprising administering a growth factor prior to or concurrently with administering the GTPase inhibitor.
10. The method of claim 9 , wherein the growth factor is G-CSF.
11. A method for mobilizing peripheral blood precursor cells from bone marrow into peripheral blood comprising: administering to a subject in need of treatment an effective amount of at least one GTPase inhibitor, wherein the GTPase inhibitor comprises an isolated fusion polypeptide comprising: a) a Rho GAP domain peptide and b) a C-terminus targeting peptide, wherein the C-terminus targeting peptide comprises the amino acid sequence of SEQ ID NO:18.
12. A method for mobilizing peripheral blood precursor cells from bone marrow into peripheral blood comprising: administering to a subject in need of treatment an effective amount of at least one GTPase inhibitor, wherein the GTPase inhibitor comprises an isolated fusion polypeptide comprising:
a) a Rho GAP domain peptide;
b) a C-terminus targeting peptide; and
c) an N-terminus membrane-translocating peptide,
wherein the amino acid sequence of the N-terminus membrane translocation peptide is Gly-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Gly-Thr-Arg-Gln-Gln-Lys-Arg-Pro, (SEQ ID NO:23).
13. A method for mobilizing peripheral blood precursor cells from bone marrow into peripheral blood comprising: administering to a subject in need of treatment an effective amount of at least one GTPase inhibitor, wherein the GTPase inhibitor comprises an isolated fusion polypeptide comprising the amino acid sequence of SEQ ID NO:11.