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Culture, device, and composition for producing adult oligodendrocyte-type 2 astrocyte progenitor cells and proliferating oligodendrocyte-type 2 astrocyte progenitor cells

Foreign code F190009871
File No. E099P05US2
Posted date Jul 29, 2019
Country United States of America
Application number 201816223724
Gazette No. 20190117704
Date of filing Dec 18, 2018
Gazette Date Apr 25, 2019
Priority data
  • P2014-008780 (Jan 21, 2014) JP
  • 2015JP51485 (Jan 21, 2015) WO
  • 201615112027 (Nov 18, 2016) US
Title Culture, device, and composition for producing adult oligodendrocyte-type 2 astrocyte progenitor cells and proliferating oligodendrocyte-type 2 astrocyte progenitor cells
Abstract The present invention provides a method for producing adult oligodendrocyte progenitor cells from proliferative oligodendrocyte progenitor cells, and a pharmaceutical composition having for an active ingredient thereof adult OPC produced according to that method. The method for producing adult OPC of the present invention is characterized by inducing proliferating OPC to differentiate into adult OPC by culturing in the presence of a ligand of a thyroid hormone receptor or retinoic acid receptor in a low oxygen environment. The present invention further provides adult OPC produced according to the production method of the present invention, and a pharmaceutical composition having these adult OPC as an active ingredient thereof.
Outline of related art and contending technology BACKGROUND ART
Oligodendrocytes are a type of glial cell found in the central nervous system that are formed by maturation of oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells (abbreviated as OPC in the present application), and are mainly responsible for the formation of myelin sheath. OPC are the products of further differentiation of glial progenitor cells that have differentiated from neural stem cells. Although OPC actively undergo repeated cell division during organogenesis, a portion of those cells mature soon after birth and begin to differentiate into oligodendrocytes, and in adults, differentiate into oligodendrocytes, with the exception of some cells (adult OPC). Adult OPC observed in adults differ from proliferating OPC observed during organogenesis and soon after birth in that they are in a dormant state without hardly any proliferation. However, adult OPC retain the ability to differentiate and differentiate into oligodendrocytes in the presence of a suitable stimulus. In other words, adult OPC are a type of somatic stem cells.
Proliferating OPC harvested from the optic nerve of rats soon after birth have been reported to not differentiate into oligodendrocytes if cultured in serum-free media containing platelet-derived growth factor (PDGF) in an environment having an oxygen concentration of 20% by volume, but differentiate into oligodendrocytes when cultured in serum-free media containing PDGF and thyroid hormone, and proliferating OPC have been reported to be able to be sub-cultured in serum-free media containing PDGF over a long period of time of one year or longer while retaining the properties of proliferating OPC but without undergoing replicative senescence (see, for example, Non-Patent Document 2). In addition, retinoic acid has been reported to induce differentiation of OPC into oligodendrocytes in the same manner as thyroid hormone, and both have been reported to function mediated by the same p53-dependent intracellular signaling pathway (see, for example, Non-Patent Document 3).
Scope of claims [claim1]
1. A culture comprising:
a serum-free medium not containing a thyroid hormone; and
proliferating OPC.

[claim2]
2. The culture according to claim 1, wherein the proliferating OPC are a primary culture or a sub-culture of OPC collected from an organism.

[claim3]
3. A device for producing adult OPC, comprising:
a composition comprising proliferating OPC and a serum-free medium; and
an oxygen concentration controller.

[claim4]
4. A device for producing proliferating OPC, comprising:
a composition comprising proliferating OPC and a serum-free medium not containing a thyroid hormone; and
an oxygen concentration controller.

[claim5]
5. The device for producing adult OPC according to claim 3, the composition further comprising a ligand of a thyroid hormone receptor or retinoic acid receptor selected from the group consisting of 3,5,3′,5′-tetraiodo-L-thyronine (T4), 3,5,3′-triiodo-L-thyronine (T3), a tetrazole compound having a structure similar to T4 or T3 and being able to bind to the thyroid hormone receptor, retinoic acid, and vitamin A.

[claim6]
6. The device for producing proliferating OPC according to claim 4, the composition further comprising a ligand of a thyroid hormone receptor or retinoic acid receptor selected from the group consisting of T4, T3, a tetrazole compound having a structure similar to T4 or T3 and being able to bind to the thyroid hormone receptor, retinoic acid, and vitamin A.

[claim7]
7. The device for producing adult OPC according to claim 3, wherein the proliferating OPC are cells obtained by primary culturing or sub-culturing OPC harvested from a living body.

[claim8]
8. The device for producing proliferating OPC according to claim 4, wherein the proliferating OPC are cells obtained by primary culturing or sub-culturing OPC harvested from a living body.

[claim9]
9. A composition comprising:
a ligand of a thyroid hormone receptor or retinoic acid receptor selected from the group consisting of T4, T3, a tetrazole compound having a structure similar to T4 or T3 and being able to bind to the thyroid hormone receptor, retinoic acid, and vitamin A;
adult OPC;
a serum-free medium; and
a gas of a low oxygen concentration.

[claim10]
10. The composition according to claim 9, wherein the oxygen concentration of the gas of a low oxygen concentration is in the range of 0.5 to 1.5% by volume.

[claim11]
11. A device for producing adult OPC, comprising:
adult OPC;
a ligand of a thyroid hormone receptor or retinoic acid receptor selected from the group consisting of T4, T3, a tetrazole compound having a structure similar to T4 or T3 and being able to bind to the thyroid hormone receptor, retinoic acid, and vitamin A;
a serum-free medium; and
an oxygen concentration controller.

[claim12]
12. The device for producing adult OPC according to claim 11, wherein the oxygen concentration controller can maintain the oxygen concentration in the range of 0.5 to 1.5% by volume, or in the range of 2.0 to 20.0% by volume, and switch the concentration from one to the other when required.
  • Inventor, and Inventor/Applicant
  • SUEMATSU Makoto
  • TOKUMOTO Yasuhito
  • TAMAKI Shinpei
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
IPC(International Patent Classification)
Reference ( R and D project ) ERATO SUEMATSU Gas Biology AREA
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