IP Library › Granted Patent US 12,227,578
Granted Patent B2
US 12,227,578 · App. 16/348,911 · Granted Feb 18, 2025

Modulation of intestinal epithelial cell differentiation, maintenance and/or function through T cell action

Inventors: Adam Haber (Cambridge, MA); Moshe Biton (Cambridge, MA); Rebecca H. Herbst (Cambridge, MA); Karthik Shekhar (Cambridge, MA); Christopher Smillie (Cambridge, MA); Orit Rozenblatt-Rosen (Cambridge, MA); Ramnik Xavier (Boston, MA); Aviv Regev (Cambridge, MA); Jose Ordovas-Montanes (Cambridge, MA); Alexander K. Shalek (Cambridge, MA); Noga Rogel (Cambridge, MA)
Assignees: The Broad Institute, Inc.; Massachussetts Institute of Technology; The General Hospital Corporation
C07K16/2833A61K35/17A61P1/04A61P1/14A61P31/04A61P33/00C07K14/47C07K14/52C07K14/71C12N5/0636C12N5/0637C12N5/0679G01N33/5044G01N33/56966G01N33/56972G01N2800/26
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Quick Facts
Patent No.
US 12,227,578
App. No.
16/348,911
Granted
Feb 18, 2025
Kind
B2
Abstract

An atlas of intestinal epithelial cells, intestinal epithelial stem cells and intestinal immune cells identifies new cell populations, markers, networks, and responses to stimuli. Intestinal T cells drive intestinal epithelial cell differentiation and activity. Accordingly, disclosed are methods of modulating intestinal epithelial cell differentiation, maintenance and/or function, related methods for the treatment of disease, including IBD. Also disclosed are methods and kits for identifying cell types, their differentiation, homeostasis and activation.

Claims (28)

1. A method of modulating intestinal epithelial cell composition in an intestinal organoid culture comprising intestinal epithelial cells, the method comprising:

co-culturing the intestinal organoid with Th1, Th2, Th17, or regulatory T (Treg) cells in an amount sufficient to modify the intestinal epithelial cell composition, whereby the Th1, Th2, Th17, or Treg cells directly influence intestinal epithelial cell proliferation, differentiation, and/or maintenance; and

detecting intestinal epithelial cells after co-culturing the intestinal organoid culture with Th1, Th2, Th17, or regulatory T (Treg) cells, whereby the intestinal epithelial cell composition is monitored, and wherein detecting intestinal epithelial cells comprises performing single cell RNA-seq (scRNA-seq) on the intestinal organoid culture.

2. The method of claim 1 , wherein the Th1, Th2, Th17, or Treg cells are added to the intestinal organoid culture in a ratio of 20 Th1, Th2, Th17, or Treg cells to each organoid in an intestinal organoid culture.

3. A method of modulating intestinal epithelial cell composition in an intestinal organoid culture comprising intestinal epithelial cells, the method comprising:

co-culturing the intestinal organoid with Th1 cells in an amount sufficient to modify the intestinal epithelial cell composition, whereby the Th1 cells directly influence intestinal epithelial cell proliferation, differentiation, and/or maintenance,

wherein expression of one or more anti-microbial peptides selected from the group consisting of Defa17, Defa24, Lyz1, Itln1, Mmp7, and Ang4 is increased in the intestinal organoid culture as compared to control organoids.

4. The method of claim 3 , wherein tuft cells are decreased in the intestinal organoid culture as compared to control organoids.

5. The method of claim 3 , wherein Paneth cells are increased in the intestinal organoid culture as compared to control organoids.

6. The method of claim 3 , wherein the Th1 cells are added to the intestinal organoid culture in a ratio of 20 Th1 cells to each organoid in an intestinal organoid culture.

7. The method of claim 3 , further comprising detecting intestinal epithelial cells after co-culturing the intestinal organoid culture with Th1 cells, wherein detecting intestinal epithelial cells comprises performing single cell RNA-seq (scRNA-seq) on the intestinal organoid culture.

8. A method of modulating intestinal epithelial cell composition in an intestinal organoid culture comprising intestinal epithelial cells, the method comprising:

co-culturing the intestinal organoid with Th1, Th2, or Th17 cells in an amount sufficient to modify the intestinal epithelial cell composition, whereby the Th1, Th2, or Th17 cells directly influence intestinal epithelial cell proliferation, differentiation, and/or maintenance,

wherein transit amplifying (TA) cells are increased in the intestinal organoid culture as compared to control organoids.

9. The method of claim 8 , wherein stem cell markers selected from the group consisting of Lgr5, Ascl2 and Smoc2 are down-regulated in the intestinal organoid culture as compared to control organoids.

10. The method of claim 8 , wherein the Th1, Th2, or Th17 cells are added to the intestinal organoid culture in a ratio of 20 Th1, Th2, or Th17 cells to each organoid in an intestinal organoid culture.

11. The method of claim 8 , further comprising detecting intestinal epithelial cells after co-culturing the intestinal organoid culture with Th1, Th2, or Th17 cells, wherein detecting intestinal epithelial cells comprises performing single cell RNA-seq (scRNA-seq) on the intestinal organoid culture.

12. A method of modulating intestinal epithelial cell composition in an intestinal organoid culture comprising intestinal epithelial cells, the method comprising:

co-culturing the intestinal organoid with regulatory T (Treg) cells in an amount sufficient to modify the intestinal epithelial cell composition, whereby the regulatory T (Treg) cells directly influence intestinal epithelial cell proliferation, differentiation, and/or maintenance,

wherein stem cell genes selected from the group consisting of Soat1, Pdgfa and Glrx are increased in the intestinal organoid culture as compared to control organoids.

13. The method of claim 12 , wherein stem cells are increased in the intestinal organoid culture as compared to control organoids.

14. The method of claim 12 , wherein the Treg cells are added to the intestinal organoid culture in a ratio of 20 Treg cells to each organoid in an intestinal organoid culture.

15. The method of claim 12 , further comprising detecting intestinal epithelial cells after co-culturing the intestinal organoid culture with Treg cells, wherein detecting intestinal epithelial cells comprises performing single cell RNA-seq (scRNA-seq) on the intestinal organoid culture.

16. A method of modulating intestinal epithelial cell composition in an intestinal organoid culture comprising intestinal epithelial cells, the method comprising:

co-culturing the intestinal organoid with Th2 cells in an amount sufficient to modify the intestinal epithelial cell composition, whereby the Th2 cells directly influence intestinal epithelial cell proliferation, differentiation, and/or maintenance,

Paneth cell gene expression is decreased in the intestinal organoid culture as compared to control organoids.

17. The method of claim 16 , wherein the Th2 cells are added to the intestinal organoid culture in a ratio of 20 Th2 cells to each organoid in an intestinal organoid culture.

18. The method of claim 16 , further comprising detecting intestinal epithelial cells after co-culturing the intestinal organoid culture with Th2 cells, wherein detecting intestinal epithelial cells comprises performing single cell RNA-seq (scRNA-seq) on the intestinal organoid culture.

Assignments (12)
CONFIRMATORY LICENSE Recorded Jul 29, 2019
From: BROAD INSTITUTE, INC.
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 049889/0657 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 16, 2019
From: ROGEL, NOGA
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049202/0808 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: HABER, ADAM
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049183/0113 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: HERBST, REBECCA H.
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049183/0167 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: ORDOVAS-MONTANES, JOSE
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 049183/0462 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: REGEV, AVIV
To: THE BROAD INSTITUTE, INC.; MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 049183/0515 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: ROZENBLATT-ROSEN, ORIT
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049183/0589 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: SHALEK, ALEXANDER K.
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 049184/0282 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: SHEKHAR, KARTHIK
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049184/0366 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: SMILLIE, CHRISTOPHER
To: THE BROAD INSTITUTE, INC.; MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 049184/0532 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: XAVIER, RAMNIK
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 049184/0684 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2019
From: BITON, MOSHE
To: THE BROAD INSTITUTE, INC.
Reel/Frame 049182/0986 →
Continuity (3)
Provisional Application 62421204 · Nov 11, 2016
Provisional Application 62533653 · Jul 17, 2017
Related Publication 20190263912A1 · Aug 29, 2019
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