IP Library › Granted Patent US 12,492,373
Granted Patent B2
US 12,492,373 · App. 17/559,458 · Granted Dec 9, 2025

Production method for nerve tissue

Inventors: Atsushi Kuwahara (Kobe, JP); Suguru Yamasaki (Kobe, JP); Yasushi Hiramine (Kobe, JP); Yoshiki Sasai (Wako, JP); Masayo Takahashi (Wako, JP)
Assignees: RACTHERA CO., LTD.; RIKEN
C12N5/062A61K35/12A61K35/30A61L27/00A61L27/383A61L27/3895C12N5/0618C12N5/0619C12N5/0621C12N5/0623C12Q1/02G01N33/5014C12N2500/99C12N2501/115C12N2501/15C12N2501/155C12N2501/16C12N2501/40C12N2501/41C12N2501/415C12N2501/727C12N2506/45C12N2533/52
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Quick Facts
Patent No.
US 12,492,373
App. No.
17/559,458
Granted
Dec 9, 2025
Kind
B2
Abstract

The present invention provides a method for producing neural cells or a neural tissue, including the following steps (1)-(3): (1) a first step of culturing pluripotent stem cells in the absence of feeder cells and in a medium containing 1) a TGFβ family signal transduction pathway inhibiting substance and/or a Sonic hedgehog signal transduction pathway activating substance, and 2) a factor for maintaining undifferentiated state, (2) a second step of culturing the cells obtained in the first step in suspension to form a cell aggregate, and (3) a third step of culturing the aggregate obtained in the second step in suspension in the presence or absence of a differentiation-inducing factor to obtain an aggregate containing neural cells or a neural tissue.

Claims (41)

1 . A method for producing cerebral cells or a cerebral tissue, comprising the following steps (1)-(3):

(1) a first step of culturing pluripotent stem cells in the absence of feeder cells and in a medium comprising (a) a Sonic hedgehog signal transduction pathway activating substance or a combination of a TGFβ family signal transduction pathway inhibiting substance and the Sonic hedgehog signal transduction pathway activating substance, and (b) a factor for maintaining an undifferentiated state of the pluripotent stem cells for a period of 0.5 hr-144 hr,

(2) a second step of culturing the cells obtained in the first step in suspension to form a cell aggregate, and

(3) a third step of culturing the aggregate obtained in the second step in suspension in the presence of a TGFβ family signal transduction pathway inhibiting substance and/or a Wnt signal transduction pathway inhibiting substance to obtain an aggregate containing cerebral cells or a cerebral tissue,

wherein the factor for maintaining an undifferentiated state of the pluripotent stem cells comprises a FGF signal transduction pathway activating substance and insulin,

wherein the FGF signal transduction pathway activating substance is bFGF,

wherein the TGFβ family signal transduction pathway inhibiting substance is Lefty, SB431542, A-83-01 or LDN193189,

wherein the Sonic hedgehog signal transduction pathway activating substance is Shh, SAG or Purmorphamine,

and wherein the Wnt signal transduction pathway inhibiting substance is IWR-1-endo.

2 . The production method according to claim 1 , wherein, in the second step, the cells obtained in the first step are dispersed, and the dispersed cells are cultured in suspension.

3 . The production method according to claim 1 , wherein, in the second step, the cells are cultured in suspension in a serum-free medium containing a Sonic hedgehog signal transduction pathway activating substance.

4 . The production method according to claim 1 , wherein the TGFβ family signal transduction pathway inhibiting substance is a Nodal/Activin signal transduction pathway inhibiting substance, a TGFβ signal transduction pathway inhibiting substance, or a BMP signal transduction pathway inhibiting substance.

5 . The production method according to claim 1 , wherein the first step is performed by an adhesion culturing method.

6 . The production method according to claim 1 , wherein, in the third step, the TGFβ family signal transduction pathway inhibiting substance and/or the Wnt signal transduction pathway inhibiting substance are/is added to the medium between day 3 and day 6 after the start of the second step.

7 . The production method according to claim 1 , wherein the pluripotent stem cells are primate pluripotent stem cells.

8 . The production method according to claim 1 , wherein the pluripotent stem cells are human pluripotent stem cells.

9 . The production method according to claim 1 , wherein the pluripotent stem cells are induced pluripotent stem cells.

10 . The production method according to claim 1 , wherein uniformed aggregates are formed in the second step.

11 . The production method according to claim 1 , wherein, in the first step, the pluripotent stem cells are cultured for a period during which pluripotent-like state of the pluripotent stem cells are maintained.

12 . The production method according to claim 11 , wherein the pluripotent-like state of the pluripotent stem cells is Oct3/4 positive.

13 . The production method according to claim 1 , wherein, in the second step and/or the third step, the culture is performed in the medium free of a factor for maintaining an undifferentiated state of the pluripotent stem cells.

14 . The production method according to claim 1 , wherein the cells obtained in the first step contain Oct3/4 positive cells at a proportion of not less than 60%.

15 . The production method according to claim 1 , wherein a period for the culturing in the second step is 12 hr-6 days.

16 . A method for producing a cerebral tissue comprising the following steps (1) and (2):

(1) a step of producing an aggregate comprising a cerebral tissue by the method of claim 1 ; and

(2) a step of cutting out a cerebral tissue from the aggregate obtained in step (1).

17 . The production method according to claim 1 , wherein the pluripotent stem cells are primed pluripotent stem cells.

18 . The production method according to claim 17 , wherein the primed pluripotent stem cells are embryonic stem cells or induced pluripotent stem cells.

19 . The production method according to claim 1 , wherein the medium comprising the factor for maintaining an undifferentiated state of the pluripotent stem cells can maintain and/or expand the pluripotent stem cells in the absence of the TGFβ family signal transduction pathway inhibiting substance or the Sonic hedgehog signal transduction pathway activating substance.

20 . A method for producing cerebral cells or a cerebral tissue, comprising the following steps (1)-(4):

(1) a first step of maintaining and/or expanding human pluripotent stem cells comprising culturing the human pluripotent stem cells in the absence of a feeder cell in a medium comprising a factor for maintaining an undifferentiated state of the pluripotent stem cells,

(2) a second step of culturing the pluripotent stem cells obtained by the first step in a medium comprising (a) a Sonic hedgehog signal transduction pathway activating substance or a combination of a TGFβ family signal transduction pathway inhibiting substance and the Sonic hedgehog signal transduction pathway activating substance, and (b) a factor for maintaining an undifferentiated state of the pluripotent stem cells in the absence of feeder cells for a period of 0.5 hr-144 hr,

(3) a third step of culturing the cells obtained in the second step in suspension to form a cell aggregate, and

(4) a fourth step of culturing the aggregate obtained in the third step in suspension in the presence of a TGFβ family signal transduction pathway inhibiting substance and/or a Wnt signal transduction pathway inhibiting substance to obtain an aggregate containing cerebral cells or a cerebral tissue,

wherein the factor for maintaining an undifferentiated state of the pluripotent stem cells comprises a FGF signal transduction pathway activating substance,

wherein the FGF signal transduction pathway activating substance is bFGF,

wherein the TGFβ family signal transduction pathway inhibiting substance is Lefty, SB431542, A-83-01 or LDN193189,

wherein the Sonic hedgehog signal transduction pathway activating substance is Shh, SAG or Purmorphamine,

and wherein the Wnt signal transduction pathway inhibiting substance is IWR-1-endo.

21 . The production method according to claim 1 , wherein the factor for maintaining an undifferentiated state of the pluripotent stem cells further comprises a TGFβ family signal transduction pathway activating substance.

22 . The production method according to claim 20 , wherein the factor for maintaining an undifferentiated state of the pluripotent stem cells further comprises a TGFβ family signal transduction pathway activating substance.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 30, 2025
From: SUMITOMO PHARMA CO., LTD.
To: RACTHERA CO., LTD.
Reel/Frame 072825/0888 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 27, 2023
From: SUMITOMO CHEMICAL COMPANY, LIMITED
To: SUMITOMO PHARMA CO., LTD.
Reel/Frame 065666/0629 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2023
From: KUWAHARA, ATSUSHI; YAMASAKI, SUGURU; HIRAMINE, YASUSHI; SASAI (LEGAL REPRESENTATIVE OF DECEASED INVENTOR YOSHIKI SASAI), MIYUKI; TAKAHASHI, MASAYO
To: SUMITOMO DAINIPPON PHARMA CO., LTD.; RIKEN; SUMITOMO CHEMICAL COMPANY, LIMITED
Reel/Frame 063798/0032 →
NAME AND ADDRESS CHANGE Recorded May 4, 2022
From: SUMITOMO DAINIPPON PHARMA CO., LTD.
To: SUMITOMO PHARMA CO., LTD.
Reel/Frame 059855/0333 →
Priority Claims (1)
JP 2014-217867 · Oct 24, 2014 · national
Continuity (2)
Continuation 15521334
Related Publication 20220112457A1 · Apr 14, 2022
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