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Activator for mesenchymal stem cells, activated mesenchymal stem cells, and method for producing same

Foreign code F180009489
File No. 13008-US01
Posted date Oct 30, 2018
Country United States of America
Application number 201515121569
Gazette No. 20170071984
Gazette No. 10512660
Date of filing Mar 11, 2015
Gazette Date Mar 16, 2017
Gazette Date Dec 24, 2019
International application number JP2015057217
International publication number WO2015137419
Date of international filing Mar 11, 2015
Date of international publication Sep 17, 2015
Priority data
  • P2014-048202 (Mar 11, 2014) JP
  • 2015JP57217 (Mar 11, 2015) WO
Title Activator for mesenchymal stem cells, activated mesenchymal stem cells, and method for producing same
Abstract [Solution] An activator for mesenchymal stem cells, mesenchymal stem cells activated by the activator, a method for producing the same, and a pharmaceutical containing the activated mesenchymal stem cells are provided.
Outline of related art and contending technology BACKGROUND OF THE INVENTION
Globally, the number of diabetic patients continuously increases. Various complications caused by chronic hyperglycemia due to diabetes threaten QOL and life of the patients, which has become a serious problem.
The so-called three major diabetic complications: diabetic nephropathy, diabetic retinopathy and diabetic neuropathy are developed due to organ damage caused by microangiopathy, which is a pathological change occurring in thin blood vessels, mainly capillaries. These complications can be prevented to a certain extent by appropriately controlling blood glucose with dietary therapy, drug therapy or the like. However, when the complications become serious, there is no fundamental therapy.
It is known that mesenchymal stem cells (hereinafter, also referred to as “MSCs”) are cells capable of differentiating into not only mesenchymal cells but also diverse cells beyond the germ layer and have an ability of controlling the tissue development, repair and reproduction.
Since the isolation and cultivation of mesenchymal stem cells are easy and mesenchymal stem cells have a vigous proliferation potential, it is possible to ensure the number of transplantable cells in a short period. In addition, mesenchymal stem cells can be transplanted autologously with no immunological rejection, which causes few ethical problems. Furthermore, allogenic transplantation of mesenchymal stem cells without pretreatment is realistic because of their low immunogenicity. Accordingly, the therapeutic applications of mesenchymal stem cells as a material for ideal cell transplant therapy for diverse diseases are proceeding.
For example, the therapeutic effects of mesenchymal stem cells have been confirmed in diabetes and its complications described above (Non Patent Literatures 1 and 2) as well as diseases such as brain and cardiovascular disease (Patent Literature 1), autoimmune disease (Non Patent Literature 3), experimental autoimmune encephalomyelitis model of multiple sclerosis (Non Patent Literature 4), and inflammatory disease (refer to Non Patent Literature 5 on pulmonary fibrosis model, refer to Non Patent Literature 6 on inflammatory bowel disease).
When used for disease therapy, it is necessary to prepare mesenchymal stem cells with a certain level of quality rapidly and in a large amount. In order to allow the mesenchymal stem cells obtained from donors to proliferate in vitro, growth promoting substances, cell culture substrates and the like are variously examined. For example, Patent Literature 2 discloses that an umbilical cord extract can be used as a serum alternative on cultivation of stem cells in a serum free medium. Concerning the quality of cells, for example, Patent Literature 3 discloses a cell growth medium for suppressing senescence of mesenchymal stem cells during subculturing.
However, the umbilical cord extract disclosed in Patent Literature 2 is simply the serum alternative. The medium in Patent Literature 3 intends to maintain the quality or suppress the degree of deterioration of mesenchymal stem cells during in vitro proliferation, and does not improve or modify the quality of mesenchymal stem cells that are not appropriate for therapy, i.e. low quality mesenchymal stem cells.
Scope of claims [claim1]
1. A method for producing activated mesenchymal stem cells in vitro, comprising:
culturing mesenchymal stem cells isolated from an individual having a disease with an effective amount of an extract prepared from a mammalian fetal appendage with an aqueous medium, wherein the disease is selected from the group consisting of diabetes and complications thereof, rheumatoid arthritis and osteoporosis, wherein said extract does not contain cells from the mammal that have proliferation potency,
wherein the expression of a gene is modified in the mesenchymal stem cells, wherein the gene is selected from the group consisting of α-smooth muscle actin (SMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, interleukin (IL)-2, Regulated on activation normal T cell expressed and secreted (RANTES), c-Jun N terminal kinase (JNK) 1/3 and insulin-like growth factor (IGF)-1, whereby the activated mesenchymal stem cells are produced.

[claim2]
2. The method according to claim 1, wherein the mammalian fetal appendage is an umbilical cord tissue, a placental tissue or a placental membrane.

[claim3]
3. The method according to claim 1, wherein the mesenchymal stem cells isolated from the individual are bone-marrow-derived mesenchymal stem cells.

[claim4]
4. The method according to claim 1, wherein the disease is diabetes or a complication thereof.

[claim5]
5. The method according to claim 1, wherein the disease is osteoporosis.

[claim6]
6. The method according to claim 1, wherein the disease is rheumatoid arthritis.

[claim7]
7. The method according to claim 1, wherein the mammalian fetal appendage is an umbilical cord tissue.

[claim8]
8. The method according to claim 1, wherein the mammalian fetal appendage is a placental tissue.

[claim9]
9. The method according to claim 1, wherein the mammalian fetal appendage is a placental membrane.

[claim10]
10. The method according to claim 1, wherein after said culturing, the expression of α-SMA, TNF-α, IL-1β, IFN-γ, IL-2, RANTES, or c-JNK 1/3 in the mesenchymal stem cells is decreased.

[claim11]
11. The method according to claim 1, wherein after said culturing, the expression of IGF-1 in the mesenchymal stem cells is increased.

[claim12]
12. The method according to claim 1, wherein the gene is α-SMA.

[claim13]
13. The method according to claim 12, wherein after said culturing, the expression of α-SMA in the mesenchymal stem cells is decreased.

[claim14]
14. The method according to claim 1, wherein the activated mesenchymal stem cells regain a therapeutic effect on treatment of the disease, wherein the disease is diabetes or a complication thereof.

[claim15]
15. The method according to claim 1, wherein the activated mesenchymal stem cells regain a therapeutic effect on treatment of the disease, wherein the disease is rheumatoid arthritis.

[claim16]
16. The method according to claim 1, wherein the activated mesenchymal stem cells regain a therapeutic effect on treatment of the disease, wherein the disease is osteoporosis.

[claim17]
17. The method according to claim 1, further comprising administering an effective amount of the activated mesenchymal stem cells to the individual.

[claim18]
18. The method according to claim 17, wherein the disease is diabetes or a complication thereof.

[claim19]
19. The method according to claim 17, wherein the disease is osteoporosis.

[claim20]
20. The method according to claim 17, wherein the disease is rheumatoid arthritis.
  • Inventor, and Inventor/Applicant
  • FUJIMIYA Mineko
  • NAGAISHI Kanna
  • MIZUE Yuka
  • CHIKENJI Takako
  • SAPPORO MEDICAL UNIVERSITY
IPC(International Patent Classification)

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