Table 3.
Differentiation factors, sequential expression of induced pluripotent stem cell-derived photoreceptor markers, and transplantation outcomes
| Disorder | Affected gene | Cell Source | Method | Differentiation factor | Cell types and markers | Drug testing/transplantation | Functional assessment | Reference |
|---|---|---|---|---|---|---|---|---|
| Retinitis Pigmentosa | USH2A variant (Arg4192His) | Keratinocytes | Sendai virus OCT4, SOX2, KLF4, c-MYC | Noggin, Dkk-1, IGF-1, bFGF, DAPT, aFGF, B27, N2 | Multilayer eyecup-like structures and retinal rosettes (recoverin, rhodopsin, B-opsin, R/G-opsin) Protein misfolding and ER stress in differentiated cells | Subretinal space; P4 immune compromised Rag1-/- x Crb1-/- mice | Extensive cellular integration and differentiated to photoreceptor cells Axonal projections toward the inner plexiform layer and the RPE layers | [72] |
| Retinitis Pigmentosa | Mutations (RP1, RP9, PRPH 2 or RHO gene) | Fibroblasts | Retroviral transduction OCT3/4, SOX2, KLF4, c-MYC | Lefty-A, Dkk-1, RA, Taurine, N2 | Immature photoreceptors (CRX, recoverin); Rod cells (rhodopsin); cone cells (opsin). ER stress in rod cells | Drug screening; Anti-oxidant vitamins (alpha-tocopherol, ascorbic acid, beta-carotene) | α-tocopherol is beneficial to RP9- mutated rod cells survival. No effect of ascorbic acid and β-carotene | [56] |
| Retinitis Pigmentosa | RHO-G188R mutation | Fibroblasts | Sendai virus OCT3/4, SOX2, KLF4, c-MYC | Lefty-A, Dkk-1, RA, Taurine | Photoreceptors precursors (recoverin, CRX); Rod cells (rhodopsin) DNA damage-inducible transcript (BiP and CHOP) expressed | Not performed | N/A | [68] |
| Undefined | Normal | Fibroblasts | Lentiviral transduction OCT4, NANOG, LIN28, SOX2 | Noggin, Dkk-1, IGF-1, N2, B27 | Photoreceptor precursors (Ot×2, Crx, recoverin, AIP1); Rod cells (rhodopsin); cone cells (S-opsin) | Subretinal Space; Adult wild-type mice along with Cyclosporine A (10 mg/kg/day) | FACS purified photoreceptor cells survived and integrated into the host retina after transplantation | [7] |
| Enhanced S-cone sensitivity syndrome (ESCS) | NR2E3 mutations | Fibroblasts | Sendai virus OCT4, SOX2, KLF4, c-MYC | IWR1e, CHIR, SAG, N2, DAPT | Photoreceptor precursors (OTX2, CRX, recoverin) Rod cells (NRL, NR2E3, RORβ, SW opsin) | Subretinal injection; Immune compromised SCID mice. | cGMP grade photoreceptor precursors cells were safe, and no intraocular tumor formed | [75] |
| MAK-associated Retinitis Pigmentosa | Homozygous for Alu insertion in MAK lacking exon 9 transcript | Fibroblasts | Lentiviral transduction OCT4, SOX2, KLF4, c-MYC | B27, N2, Noggin, Dkk-1, IGF1, bFGF, DAPT, aFGF | Photoreceptor precursors (OTX2, recoverin) | Not performed | MAK exon 12 is retina-specific, but not MAK exon 9 Point mutations in exon 9 and 12 are not a common cause | [76] |
| Undefined | N/A | Fibroblasts | Retroviral transduction OCT4, SOX2, KLF4, MYC | CKI-7, SB-431542, N2, RA, Taurine | Photoreceptor precursors (CRX, NRL recoverin) Rod cells (rhodopsin) | Not performed | N/A | [77] |
| Undefined | N/A | Fibroblasts | Retroviral transduction OCT4, SOX2, KLF4, MYC | Dkk-1, Lefty A, N2, RA, Taurine | Photoreceptor precursors (CRX, recoverin) Rod cells (rhodopsin) | Not performed | N/A | [78] |
| Undefined | N/A | Fibroblasts | Retroviral transduction OCT4, SOX2, KLF4, LIN-28 | B27, N2, Noggin, Dkk-1, Lefty A, IGF1, SHH, T3, RA, Taurine | Photoreceptor precursors (CRX, recoverin, arrestin 3) Rod cells (Rhodopsin); cone-specific opsin blue and opsin red/green | Not performed | N/A | [79] |
| Undefined | N/A | Corneal fibroblast | STEMCAA lentivirus OCT4, SOX2, KLF4, MYC | B27, N2, RA, Taurine, bFGF, aFGF, SHH | Photoreceptor precursors (CRX, recoverin) Rod cells (NRL, NR2E3, RORβ, SW opsin) | Not Performed | N/A | [80] |
| Undefined | N/A | hiPSC lines; fibroblasts, cord blood, keratinocytes | Lentivirus SOX2, OCT4, NANOG, LIN28. Episomes SOX2, OCT4, KLF4, MYC, NANOG, LIN28, SV40T | Heparin, N2, B27, Taurine, RA | Photoreceptor precursors (Ot×2, recoverin) Rod cells (rhodopsin); cone cells (S-opsin, L/M-opsin) | Not Performed | Retinal organoids acquired mature photoreceptors with functional domains containing an outer segment disc that were responsive to lights | [57] |
| Healthy donor | N/A | Blood (activated T cells) | Retroviral transduction; 3 bicistronic MMLV constructs: (OCT4, SOX2), (c-MYC, KLF4), and (NANOG, LIN28) | Heparin, N2, B27 | Photoreceptor precursors (CRX, recoverin) Rod cells (rhodopsin); cone cells (S-opsin) | Not performed | In vitro synaptogenesis was recapitulated in hiPSC-derived optic vesicles. CX36 required for electrical synapses were upregulated in optic vesicles | [65] |
| Gyrate atrophy | N/A | hiPSC lines, gyrate atrophy fibroblasts | Lentiviral transduction OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4 | Noggin, Dkk-1 B27, N2 | Photoreceptor precursors (OTX2, CRX, NRL recoverin) Phototransduction (CNGA1, A3, B1 and B3, RETGC, ODE6B, arrestin). Photoreceptor-like cells showed electrophysiological responses | Not Performed | Gene-corrected hiPSC-RPE showed normal level of ornithine-δ-aminotransferase (OAT) activity | [81] |
| Retinitis pigmentosa | Rhodopsin mutation (E181K) | Fibroblasts | Retroviral transduction OCT3/4, SOX2, KLF4, c-MYC | N2, Noggin, Dkk-1, IGF-1 | NRL-positive rod cells DNA damage-inducible transcript (BiP and CHOP) expressed, Rhodopsin E181K mutation was responsible for the loss of rod cells | Drug Screening: mTOR inhibitors (rapamycin and PP242), AMPK activators (AICAR), ASK1 inhibitors (NQDI-1), and inhibitors for eIF2α phosphatase and protein synthesis (salubrinal) | Suppression of E181K mutant rhodopsin-related cell loss by mTOR inhibition, AMPK activation, ASK1 inhibition, or the suppression of protein synthesis | [82] |
| Undefined | N/A | hiPS cell lines (IMR90 clone 4) | N/A | N2, Heparin, B27, BMP4, Wnt3A, SU5402 | Photoreceptor precursors (CRX, recoverin) Cone-specific opsin | Not performed | N/A | [83] |
| Undefined | N/A | hiPS cell lines | mRNA reprogramming Kit, Episomal vectors | B27, N2, Insulin, Noggin, BDNF, CNTF, RA, DAPT | Photoreceptor progenitors (CRX, NRL, NR2E3), Rod cells (rhodopsin, recoverin, and phosphodiesterase 6 alpha) | Subretinal space; Rd1 mice with end-stage retinal degeneration | Differentiated into cell photoreceptors, formed cell layer, interact with host retina and visual functions was partially restored | [74] |
| Undefined | N/A | Fibroblasts | OriP/EBNA1-based episomal vectors pEP4EO2SEN2K, pEP4EO2SET2K, and pCEP4-M2L | N2, FGF2, DAPT | Photoreceptor precursors (OTX2, CRX, NRL recoverin) Rod cells (rhodopsin); cone cells (blue opsin, R/G-opsin, cone arrestin) | Not performed | Notch pathway inhibition accelerated the generation of photoreceptor precursors | [84] |
| None | N/A | hiPS cell line (NCL1), cord blood-derived CD34+ | Episomal plasmids | N1, Dkk-1, Noggin, IGF1, IWR1, SB431542, LDN193189 | Photoreceptor precursors (OTX2, CRX, BLIMP1, AIPL1, recoverin) Rod cells (NRL); cone cells (RXRγ) | Subretinal space; IL2rγ-/- mice (B6.129S4-Il2rgtm1Wjl/J) | Photoreceptor precursor cells integrated into the host retina with synaptic end-feet to plexiform layer | [85] |
| None | N/A | hiPS cell line (IMR90-4) | N/A | B27, Taurine, RA, N2 | Photoreceptor precursors (Recoverin) Rod cells (CD133/CD73, Rhodopsin); cone cells (S-opsin, L/M-opsin, cone arrestin) | Not performed | Bioreactor culture conditions improved retinal lamination and increased the yield of photoreceptors | [86] |
| None | N/A | hiPS cell line (H9, H1, IMR90-4) | N/A | N2, B27, Taurine, RA | Photoreceptor precursors (OTX2, CRX, NRL recoverin) Rod cells (rhodopsin); cone cells (S-opsin, L/M-opsin, arrestin 3, RXRγ) | Subretinal space; Cone cells transplantation into Nrl-/-, and Aipl1-/- mice | Cone precursors incorporated into host cone-rich retina. Also, cones have the potential to replace lost photoreceptors in end-stage retinal degeneration | [87] |
| None | N/A | hiPS cell line (hiPSC-2 clone), fibroblasts | N/A | N2, B27, FGF2 | Photoreceptor precursors (CRX, Recoverin, CD73) Rod cells (rhodopsin); cone cells (blue opsin, R/G-opsin) | Trans-vitreal injection; hemizygous P23H rats along Cyclosporine A (210mg/L) | Transplantation of CD73+cells showed no significant functional improvement | [88] |
| Healthy donor | N/A | hiPS cell lines (UE017, UE022, and UC005), urine cells | N/A | B27, N2, Taurine | Photoreceptor precursors (OTX2) Rod cells (rhodopsin); cone cells (S-opsin, L/M-opsin) | Not performed | Matured rod and cone cells acquisition in retinal organoids without the addition of RA | [89] |
| None | N/A | NHEK primary cell line | Sendai virus OCT4, SOX2, KLF4, c-MYC | B27, N2, DAPT, Taurine, RA | Photoreceptor precursors (OTX2, CRX, recoverin) Rods cells (rhodopsin); cone cells (B-opsin, R/G-opsin) | Not performed | Aberrant-hiPSC differentiated into retinal organoids that acquired matured photoreceptors | [90] |
N/A: Not available