United States Patent 10,960,025
Aggarwal, et al.
March 30, 2021
Mesenchymal stem cells and uses therefor
Abstract Compositions and methods of promoting wound healing in a human by administering to the human mesenchymal stem cells in an effective amount.
Inventors: Aggarwal; Sudeepta (North Potomac, MD), Pittenger; Mark F. (Severna Park, MD), Varney; Timothy (Baltimore, MD)
Applicant: Mesoblast International Sarl Meyrin N/A CH
Assignee:Mesoblast International Sarl (Meyrin, CH)
Family ID: 1000005452014
Appl. No.: 16/811,900
Filed: March 6, 2020
The invention claimed is:
1. A method of treating inflammatory bowel disease in a patient, the method comprising administering to the patient a suspension of isolated, cultured, genetically unmanipulated mesenchymal stem cells, in an amount effective to limit the inflammation in the gut and treat the inflammatory bowel disease.
2. The method of claim 1, wherein the mesenchymal stem cells are allogeneic.
3. The method of claim 1, wherein the mesenchymal stem cells are autologous.
4. The method of claim 1, wherein the suspension further comprises an acceptable pharmaceutical carrier.
5. The method of claim 1, wherein the suspension is administered in an amount of from about 1.times.10.sup.5 cells/kg to about 1.times.10.sup.7 cells/kg.
6. The method of claim 1, wherein the suspension is administered in an amount of from about 1.times.10.sup.6 cells/kg to about 5.times.10.sup.6 cells/kg.
7. The method of claim 1, wherein the cultured, genetically unmanipulated mesenchymal stem cells are isolated from marrow.
8. The method of claim 7, wherein the marrow is iliac crest marrow.
9. The method of claim 1, wherein the mesenchymal stem cells increase secretion of interleukin-10.
10. The method of claim 1, wherein the mesenchymal stem cells increase generation of regulatory T cells.
11. The method of claim 1, wherein the patient is human and the mesenchymal stem cells are human.
12. The method of claim 2, wherein the patient is human and the mesenchymal stem cells are human.
13. The method of claim 3, wherein the patient is human and the mesenchymal stem cells are human.
14. The method of claim 1, wherein the mesenchymal stem cells were isolated from blood, skin, cord blood, muscle, fat, bone, or perichondrium.
BACKGROUND OF THE INVENTION
This invention relates to mesenchymal stem cells. More particularly, this invention relates to novel uses for mesenchymal stem cells, including promoting angiogenesis in various tissues and organs, treating autoimmune diseases, treating allergic responses, treating cancer, treating inflammatory diseases and disorders, promoting would healing, treating inflammation, and repairing epithelial damage.
Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate readily into lineages including osteoblasts, myocytes, chondrocytes, and adipocytes (Pittenger, et al., Science, Vol. 284, pg. 143 (1999); Haynesworth, et al., Bone, Vol. 13, pg. 69 (1992); Prockop, Science, Vol. 276, pg. 71 (1997)). In vitro studies have demonstrated the capability of MSCs to differentiate into muscle (Wakitani, et al., Muscle Nerve, Vol. 18, pg. 1417 (1995)), neuronal-like precursors (Woodbury, et al., J. Neurosci. Res., Vol. 69, pg. 908 (2002); Sanchez-Ramos, et al., Exp. Neurol., Vol. 171, pg. 109 (2001)), cardiomyocytes (Toma, et al., Circulation, Vol. 105, pg. 93 (2002); Fakuda, Artif. Organs, Vol. 25, pg. 187 (2001)) and possibly other cell types. In addition, MSCs have been shown to provide effective feeder layers for expansion of hematopoietic and embryonic stem cells (Eaves, et al., Ann. N.Y. Acad. Sci., Vol. 938, pg. 63 (2001); Wagers, et al., Gene Therapy, Vol. 9, pg. 606 (2002)). Recent studies with a variety of animal models have shown that MSCs may be useful in the repair or regeneration of damaged bone, cartilage, meniscus or myocardial tissues (DeKok, et al., Clin. Oral Implants Res., Vol. 14, pg. 481 (2003)); Wu, et al., Transplantation, Vol. 75, pg. 679 (2003); Noel, et al., Curr. Opin. Investig. Drugs, Vol. 3, pg. 1000 (2002); Ballas, et al., J. Cell. Biochem. Suppl., Vol. 38, pg. 20 (2002); Mackenzie, et al., Blood Cells Mol. Dis., Vol. 27 (2002)). Several investigators have used MSCs with encouraging results for transplantation in animal disease models including osteogenesis imperfecta (Pereira, et al., Proc. Nat. Acad. Sci., Vol. 95, pg. 1142 (1998)), parkinsonism (Schwartz, et al., Hum. Gene Ther., Vol. 10, pg. 2539 (1999)), spinal cord injury (Chopp, et al., Neuroreport, Vol. 11, pg. 3001 (2000); Wu, et al., J. Neurosci. Res., Vol. 72, pg. 393 (2003)) and cardiac disorders (Tomita, et al., Circulation, Vol. 100, pg. 247 (1999). Shake, et al., Ann. Thorac. Surq., Vol. 73, pg. 1919 (2002)). Importantly, promising results also have been reported in clinical trials for osteogenesis imperfecta (Horwitz, et al., Blood, Vol. 97, pg. 1227 (2001); Horowitz, et al. Proc. Nat. Acad. Sci., Vol. 99, pg. 8932 (2002)) and enhanced engraftment of heterologous bone marrow transplants (Frassoni, et al., Int. Society for Cell Therapy, SA006 (abstract) (2002); Koc, et al., J. Clin. Oncol., Vol. 18, pg. 307 (2000)).
MSCs express major histocompatibility complex (MHC) class I antigen on their surface but do not express MHC class II (Le Blanc, et al., Exp. Hematol., Vol. 31, pg. 890 (2003); Potian, et al., J. Immunol., Vol. 171, pg. 3426 (2003)) and no B7 or CD40 co-stimulatory molecules (Majumdar, et al., J. Biomed. Sci., Vol. 10, pg. 228 (2003)), suggesting that these cells have a low-immunogenic phenotype (Tse, et al., Transplantation, Vol. 75, pg. 389 (2003)). MSCs also inhibit T-cell proliferative responses in an MHC-independent manner (Bartholomew, et al., Exp. Hematol., Vol. 30, pg. 42 (2002); Devine, et al., Cancer J., Vol. 7, pg. 576 (2001); DiNicola, et al., Blood, Vol. 99, pg. 3838 (2002)). These immunological properties of MSCs may enhance their transplant engraftment and limit the ability of the recipient immune system to recognize and reject allogeneic cells following transplantation. The production of factors by MSCs, that modulate the immune response and support hematopoiesis together with their ability to differentiate into appropriate cell types under local stimuli make them desirable stem cells for cellular transplantation studies (Majumdar, et al., Hematother. Stem Cell Res., Vol. 9, pg. 841 (2000); Haynesworth, et al., J. Cell. Physiol., Vol. 166, pg. 585 (1996).
BRIEF SUMMARY OF THE INVENTION
Applicants presently have examined the interactions of mesenchymal stem cells with isolated immune cell populations, including dendritic cells (DC1 and DC2), effector T-cells (Th1 and Th2), and NK cells. Based on such interactions, Applicants discovered that mesenchymal stem cells may regulate the production of various factors that may regulate several steps in the immune response process. Thus, the mesenchymal stem cells may be employed in the treatment of disease conditions and disorders involving the immune system, or diseases, conditions, or disorders involving inflammation, epithelial damage, or allergic responses. Such diseases, conditions, and disorders include, but are not limited to, autoimmune diseases, allergies, arthritis, inflamed wounds, alopecia araeta (baldness), periodontal diseases including gingivitis and periodontitis, and other diseases, conditions or disorders involving an immune response.
In addition, it is believed that mesenchymal stem cells express and secrete vascular endothelial growth factor, or VEGF, which promotes angiogenesis by stimulating the formation of new blood vessels. Mesenchymal stem cells also stimulate peripheral blood mononuclear cells (PBMCs) to produce VEGF.
Furthermore, it is believed that mesenchymal stem cells stimulate dendritic cells (DCs) to produce Interferon-Beta (IFN-.beta.), which promotes tumor suppression and immunity against viral infection.
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