Trans-differentiation of differentiation cells

1. A method of trans-differentiating differentiated cells selected from fibroblasts and astrocytes into neurons, the method comprising contacting or introducing into said differentiated cells at least one component (i) and at least one component (ii),

wherein said component (i) is selected from group consisting of:

(a) a polypeptide of the Bcl-2 family, said polypeptide of the Bcl-2 family being selected from the group consisting of: human Bcl-2 having the sequence of SEQ ID NO: 1, human Bcl-2 having the sequence of SEQ ID NO: 5, and murine Bcl-2 having the sequence of SEQ ID NO: 3; a nucleic acid encoding said polypeptide; or forskolin at a concentration that enhances the amount and/or activity of said polypeptide in said differentiated cells;

(b) a polypeptide comprising the amino acid sequence of a wild-type form of a member of the Bcl-2 family or a fragment thereof, said wild-type form of a member of the Bcl-2 family being selected from the group consisting of: human Bcl-2 having the sequence of SEQ ID NO: 1, human Bcl-2 having the sequence of SEQ ID NO: 5, murine Bcl-2 having the sequence of SEQ ID NO: 3, and human Bcl-X L having the sequence of SEQ ID NO: 6, wherein the fragment has at least 98% sequence identity with the wild-type form and wherein said wild-type form has anti-apoptotic activity; a nucleic acid encoding said polypeptide; or a forskolin at a concentration that enhances the amount and/or activity of said polypeptide in said differentiated cells;

(c) a polypeptide comprising the amino acid sequence of a wild-type form of a member of the Bcl-2 family or a fragment thereof, said wild-type form of a member of the Bcl-2 family being selected from the group consisting of: human Bcl-2 having the sequence of SEQ ID NO: 1, human Bcl-2 having the sequence of SEQ ID NO: 5, murine Bcl-2 having the sequence of SEQ ID NO: 3, and human Bcl-X L having the sequence of SEQ ID NO: 6, wherein said polypeptide comprises one or more point mutations as compared to said wild-type form or fragment thereof, wherein the fragment has at least 98% sequence identity with the wild-type form, wherein said wild-type form has anti-apoptotic activity, wherein one or more phosphorylatable residues in a flexible loop domain are replaced by non-phosphorylatable residues in said polypeptide; or forskolin at a concentration that enhances the amount and/or activity of said polypeptide in said differentiated cells; and

(d) a polypeptide comprising an amino acid sequence which exhibits at least 98% sequence identity with a wild-type form of a member of the Bcl-2 family, wherein said wild-type form has anti-apoptotic activity, said wild-type form of a member of the Bcl-2 family being selected from the group consisting of: human Bcl-2 having the sequence of SEQ ID NO: 1, human Bcl-2 having the sequence of SEQ ID NO: 5, murine Bcl-2 having the sequence of SEQ ID NO: 3, and human Bcl-X L having the sequence of SEQ ID NO: 6, wherein one or more phosphorylatable residues in a flexible loop domain are replaced by non-phosphorylatable residues in said polypeptide; a nucleic acid encoding said polypeptide; or forskolin at a concentration that enhances the amount and/or activity of said polypeptide in said differentiated cells;

wherein said component (i) enhances the yield of neurons by at least 30% as compared to the absence of said component (i); and

wherein said component (ii) is one or more neurogenic transcription factors, said transcription factors being Ascl1 and/or Neurog2.

2. The method of claim 1 , further comprising contacting or introducing into said differentiated cells at least one component (iii), wherein component (iii) reduces lipid peroxidation and is selected from the group consisting of:

(a) vitamin D receptor, a functional homolog thereof, or a nucleic acid encoding said receptor or said homolog thereof;

(b) a steroid antioxidant;

(c) a phenol antioxidant; and

(d) a quinine.

3. The method of claim 1 , wherein said polypeptide as defined in (b), (c), or (d) has reduced anti-apoptotic function as compared to said human Bcl-2 of (a); and/or wherein said polypeptide as defined in (b), (c), or (d) enhances the yield of neurons to a greater degree than said human Bcl-2 of (a).

4. The method of claim 1 , wherein said polypeptide as defined in (c) or (d) of claim 1 is selected from a Bcl-2 mutant which

(a) differs from wild type Bcl-2 in that one or more phosphorylatable residues in the flexible loop domain are replaced by non-phosphorylatable residues or deleted, the Bcl-2 mutant being selected from

(i) the S70A mutant of human Bcl-2;

(ii) the T69A/S70A double mutant of human Bcl-2;

(iii) the S87A mutant of human Bcl-2;

(iv) the T69A/S70A double mutant of human Bcl-2;

(v) the T69A/S87A double mutant of human Bcl-2;

(vi) the S70A/S87A double mutant of human Bcl-2;

(vii) the T69A/S70A/S87A triple mutant of human Bcl-2;

(viii) deletion mutants selected from the deletion of one, two or three of T69, S70 and S87 of human Bcl-2; and

(ix) the aa 69 to 87 deletion mutant of human Bcl-2; or

(b) is a mutant of human Bcl-2 having the transmembrane region deleted or rendered non-functional,

wherein human Bcl-2 has the sequence set forth in SEQ ID NO: 1 or 5.

5. The method of claim 1 , wherein said differentiated cells are (i) of vertebrate origin; and/or (ii) from an embryonic- or post-natal stage.

6. The method of claim 5 , wherein said differentiated cells are fibroblasts.

7. The method of claim 6 , wherein said one or more neurogenic transcription factors are Ascl1 and Neurog 2 and the method yields one or more neurons selected from the group consisting of inhibitory neurons, excitatory neurons, and cholinergic neurons.

8. The method of claim 7 , wherein the one or more trans-differentiated cells are selected from GABAergic neurons, glutamatergic neurons, and motor neurons.