Methods for stimulating hematopoietic recovery by inhibiting TGFβ signaling
This disclosure demonstrates that blockade of TGFβ signaling after a hematopoietic stress (e.g., chemotherapy, transplantation, and infection) accelerates hematopoietic reconstitution and delays the return of cycling hematopoietic stem and progenitor cells (HSPCs) to quiescence. TGFβ blockade in these settings promotes multilineage hematopoietic regeneration by prolonging HSPC cycling and by promoting HSC self-renewal, and is useful for treating hematologic deficiencies caused various hematopoietic stresses.
1. A method of promoting hematopoietic recovery in a subject, comprising administering a TGFβ signaling inhibitor to the subject, wherein said subject is a cancer patient undergoing chemotherapy with a chemotherapeutic drug, and wherein the TGFβ signaling inhibitor is administered to the subject at least one day after the administration of the chemotherapeutic drug and before the activation of the TGFβ signaling in the bone marrow and within 10 days after the administration of the chemotherapeutic drug.
2. The method of claim 1 , wherein the TGFβ signaling inhibitor is administered to the subject at least 2-3 days day after the administration of the chemotherapeutic drug.
3. The method of claim 1 , wherein the chemotherapeutic drug is administered to the cancer patient in a higher dosing scheme as compared to the dosing scheme without the TGFβ-pathway inhibitor.
4. The method of claim 3 , wherein said higher dosing scheme is selected from a higher dosage amount per dose, a more frequent dosing schedule, a longer treatment cycle, or a combination thereof.
5. The method of claim 1 , wherein said subject is undergoing hematopoietic stem cell transplant.
6. The method of claim 1 , wherein said subject is suffering an infection which causes hematopoietic stress and/or deficiencies.
7. The method of claim 1 , wherein said TGFβ signaling inhibitor is an antibody which antagonizes the interaction and binding between TGFβ and TGFβ receptor.
8. The method of claim 1 , wherein said TGFβ signaling inhibitor is a soluble polypeptide composed of the extracellular domain of a TGFβ receptor.
9. The method of claim 1 , wherein said TGFβ signaling inhibitor is an oligonucleotide selected from the group consisting of an antisense, RNAi, dsRNA, siRNA and ribozyme molecule.
10. The method of claim 1 , wherein said TGFβ signaling inhibitor inhibits TGFβ Receptor kinase activity.
11. The method of claim 1 , wherein said TGFβ signaling inhibitor antagonizes the activation of latent TGFβ to its active form capable of binding to a TGFβ receptor.
12. The method of claim 1 , wherein the TGFβ signaling inhibitor is administered to the subject within 7 days after the administration of the chemotherapeutic drug.