Compositions and methods for generating hair cells by upregulating JAG-1

1. A method for increasing proliferation of a cochlear supporting cell or a vestibular supporting cell, comprising contacting the supporting cell with CHIR99021, and

a Jagged-1 (Jag-1) agonist, wherein the Jag-1 agonist is a HIF1-α activator, wherein the HIF1-α activator is 4,4α-dihydro-4-oxo-1,10-phenanthroline-3-carboxylic acid (1,4-DPCA), N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine (FG-2216) or N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine (daprodusat).

2. A method for producing an expanded population of cochlear or vestibular cells, comprising contacting a population of cochlear supporting cells or vestibular supporting cells with CHIR99021, and

a Jagged-1 (Jag-1) agonist, wherein the Jag-1 agonist is a HIF1-α activator, wherein the HIF1-α activator is 4,4α-dihydro-4-oxo-1,10-phenanthroline-3-carboxylic acid (1,4-DPCA), N-[(1-chloro-4-hydroxy-3-isoquinolinyl)carbonyl]-glycine (FG-2216) or N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]-glycine (daprodusat).

3. The method of anyone of claim 1 , wherein the cochlear supporting cell or vestibular supporting cell expresses leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5).

4. The method of claim 1 , wherein the cochlear supporting cell or vestibular supporting cell is a mature cell.

5. The method of claim 1 , wherein the cochlear supporting cell or vestibular supporting cell is a cochlear supporting cell.

6. The method of claim 1 , wherein the CHIR99021 and HIF1-α activator are administered locally and/or systemically.

7. The method of claim 6 , wherein the local administration is to the tympanic membrane, the middle ear or the inner ear.

8. The method of claim 6 , wherein the systemic administration is oral or parenteral.

9. The method of claim 1 , wherein:

1,4-DPCA is administered at a concentration of between 1 nM to 100 mM;

FG-2216 is administered at a concentration of between 1 nM to 1000 mM; or

daprodusat is administered at a concentration of between 1 nM to 1000 mM.

10. The method of claim 1 , wherein CHIR99021 is at a concentration of about between 1 μM to 10 μM.

11. The method of claim 1 , wherein the CHIR99021 and HIF1-α activator are in a biocompatible matrix.

12. The method of claim 1 , wherein the biocompatible matrix comprises hyaluronic acid, hyaluronates, lecithin gels, pluronics, poly(ethyleneglycol), poloxamers, chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides), poly(glycolide), poly(lactic-co-glycolic acid (PLGA), sucrose acetate isobutyrate, glycerol monooleate, poly anhydrides, poly caprolactone sucrose, glycerol monooleate, silk materials, or a combination thereof.

13. The method of claim 1 , further comprises contacting the supporting cell with valproic acid.

14. The method of claim 2 , further comprises contacting a population of cochlear supporting cells or vestibular supporting cells with valproic acid.