Establishing Functional Retina in a Dish: Progress and Promises of Induced Pluripotent Stem Cell-Based Retinal Neuron Differentiation
Abstract
:1. Introduction
2. Retinal Neuron Differentiation from iPSCs
2.1. Differentiation of iPSC-Derived Retinal Organoids
2.1.1. Generation of Storable Retinal Organoids under Chemically Defined Conditions
2.1.2. The Role of Retinoic Acid in Retinal Organoid Differentiation
2.1.3. Enhancement of Rod Photoreceptor Differentiation in Retinal Organoids through 9-cis Retinal Supplementation
2.1.4. Effects of BMP4 Treatment on the Yield and Cellular Composition of Organoid Differentiation
2.1.5. Different Approaches for Isolating Optic Vesicle-like Structures during Differentiation
2.2. Retinal Ganglion Cell Differentiation from iPSCs
2.2.1. Generation of Functional RGCs under Chemically Defined Culture Conditions
2.2.2. Enhancing RGC Differentiation and Neurite Outgrowth through Biomaterial Incorporation
2.2.3. Efficient Protocol for RGC Generation through Dual SMAD and Wnt Inhibition
2.2.4. Generation of RGCs through Dissociation of Retinal Organoids and Magnetic-Activated Cell Sorting
2.2.5. A Rapid Protocol for RGC Differentiation Using NGN2 Overexpression
2.3. Photoreceptor Cell Differentiation from iPSCs
2.3.1. Generation of Photoreceptors under Defined Conditions Using Signaling Modulators
2.3.2. Photoreceptor Differentiation without Using Extrinsic Signaling Modulators
2.3.3. Photoreceptor Differentiation Induced by Small-Molecule Inhibitors
2.3.4. Enhancing Yield and Maturation of Photoreceptor Cells by Using a Bioreactor
3. Detection of Molecular Markers to Confirm Retinal Cell Identity
3.1. Molecular Markers for Evaluating Retinal Organoid Differentiation
3.2. Molecular Markers for Evaluating Retinal Ganglion Cell Differentiation
3.3. Molecular Markers for Evaluating Photoreceptor Cell Differentiation
3.4. Other Techniques and Functional Assays for Evaluating Retinal Neuron Differentiation
4. Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Authors | Year | Cell Source | Differentiation Procedures | Differentiation Culture Media | Differentiation Factors | Immunostaining Maker | Time Length | Other Assays |
---|---|---|---|---|---|---|---|---|
Reichman et al. [16] | 2017 | hiPSC | NR, RO | Essential 6 medium, ProB27 medium | N2 supplement, FGF2 | RPC: VSX2, Ki67 Photoreceptor: CRX, NRL, NEUROD1, RCVRN, CAR, RHO, OPN1SW, OPN1L/MW, CD73, OTX2 RGC: BRN3A, PAX6 AC: AP2, PAX6 HC: LIM1, PAX6 BC: PKCα, VSX2 MC: GLUTAMIN SYNTHASE, SOX9 | 28–280 days | qPCR: Eye field specification: SIX3, MITF, VSX2, PAX6, RAX, LHX2 Photoreceptor lineage: NRL, CRX, NEUROD1, RCVRN, CAR Mature photoreceptor: RHO, OPN1SW, OPN1L/MW RGC: BRN3A, BRN3B AC: GAD2 HC: LIM1 BC: PKCα MC: GLAST1, RLBP1 |
Li et al. [32] | 2018 | Urine cell-derived hiPSC | EB, RO | mTeSR1 medium, NIM, RDM | Blebbistatin, FBS, Taurine, GlutaMAX | Eye field fate: SOX1, PAX6, OTX2, LHX2, SIX3 RPC: VSX2(CHX10), MCM2 RGC: BRN3 AC: AP2 HC: PROX1 BC: PKCα MC: CRALBP Photoreceptor: RHO, OPN1SW, OPN1L/MW, RCVRN, PDE6α, GNAT1 | 6 weeks | RT-PCR: Eye field transcription factor: PAX6, LHX2, RAX, SIX3, SIX6 |
Kaya et al. [33] | 2019 | hiPSC | EB, OV, RO | E8 medium, NIM, PIM | Y-27632, FBS, taurine, GlutaMAX, retinoid, N2 supplement, IGF-1, beta-mercaptoethanol, 9-cis retinal, ATRA | RPC: VSX2(CHX10) RGC: BRN3A Pan-photoreceptor: RCVRN Photoreceptor: CRX Rod: RHO Cone: OPN1L/MW, OPN1SW AC/HC: CALB BC: PKCα MC: CRALBP Ribbon synapses: Bassoon | 200 days | Western blot: Rod photoreceptor: RHO |
Capowski et al. [34] | 2019 | hiPSC | EB, OV, RO | NIM, RDM | BMP4, FBS, taurine, chemically defined lipid supplement, ATRA | Early retinogenesis: VSX2, Ki67 RGC: BRN3B, SNCG Photoreceptor precursors: OTX2 Photoreceptor: CRX, RCVRN Cone: ARR3, OPN1L/MW, OPN1SW Rod: NRL, NR2E3, RHO Photoreceptor pre-synaptic marker: VGLUT1, CTBP2 HC: OC1 AC: CaR BC: PKCα, GNAO1 | 175 days | Optical coherence tomography (OCT) |
Regent et al. [35] | 2020 | hiPSC | EB, OV, RO | E8 or mTeSR1 medium, NIM, RIM | Y-27632, B27 supplement without vitamin A, GlutaMAX, IGF-1, FBS, taurine, 9-cis retinal, N2 supplement | RPC: CHX10 RGC: BRN3A Photoreceptor: ARL13B, PCNT, RCVRN Rod: RHO Cone: OPN1SW, OPN1L/MW AC/HC: CALB MC: CRALBP BC: PKCα | 200 days | NA |
Berber et al. [36] | 2021 | hiPSC | EB, RO | Method (1) mTeSR Plus medium, BE6.2 medium, LTR medium Method (2&3) mTeSR Plus medium, NIM, RDM, RC2 medium, RC1 medium | Method (1) Blebbistatin, IWR-1e, SAG, ATRA, DAPT Method (2) Blebbistatin, HEPES, ATRA Method (3) Blebbistatin, HEPES, ATRA, BMP4 | RPC: VSX2 RGC: BRN3A, SNCG Photoreceptor: CRX, RCVRN Rod: RHO Cone: OPN1SW AC: AP2 | 85 days | NA |
Sanjurjo-Soriano et al. [37] | 2022 | hiPSC | NR, RO | E6 medium, RDM | Method (1) N-2 supplement, FGF2 Method (2) N-2 supplement, FGF2, FBS, B27 supplement without vitamin A Method (3) N-2 supplement, FGF2, FBS, B27 supplement without vitamin A, taurine, RA | Photoreceptor: CRX, RCVRN, NR2E3 Rod: RHO Cone: ARR3, OPN1SW | 85 days | qPCR: ARR3, BRN3A, CRX, GAD2, GLAST1, LIM1, NRL, NR2E3, OPN1MW, OTX2, PKCα, RAX, RCVRN, RHO, GRK1, SIX3, VSX2 Western blot: anti-PDE6B, anti-β-tubulin |
Authors | Year | Cell Source | Differentiation Procedures | Differentiation Culture Media | Differentiation Factors | Markers | Time Length | Functional Assays | Efficiency | Tests for Efficiency |
---|---|---|---|---|---|---|---|---|---|---|
Teotia et al. [50] | 2017 | mESC, hiPSC | EB, neural-rosettes, RPC, RGC | NIM, neural expansion medium | Noggin, DKK1, glutamine, N2, B27, bFGF, IGF-1, SHH, FGF8, DAPT, follistatin, cyclopamine, BDNF, forskolin, NT4, CNTF, cAMP, Y-27632 | ATOH7, BRN3B, bIII-tubulin, THY1, GAP43, ISL1, RAX, PAX6, VSX2(CHX10) | 58 days | Electro-physiological responses (patch-clamp recording) | 84.5 ± 13.0% (ATOH7+) 68.4 ± 18.6% (BRN3+) | ICC |
Lee et al. [51] | 2018 | hiPSC | EB, neural rosettes, RGC | Human ESC medium (-bFGF), N2 medium, N2B27 medium | Dorsomorphin, SB341542, XAV939, IGF-1, N2, B27, insulin, bFGF, DAPT, BDNF | PAX6, LHX2, MATH5, BRN3B, ISL1, TUJ1(TUBB3), NF-L, THY1, SNCG | 40 days | Electro-physiological responses (patch-clamp recording) | 45% (BRN3B+ ISL1+) | IHC |
Langer et al. [52] | 2018 | hiPSC | EB, retinal organoid, RGC | NIM, RDM, BrainPhys Neuronal Medium | N2, B27, heparin, FBS | RGC: BRN3, ISL1, RBPMS, SNCG α-RGC: KCNG4, CB2, SPP1 DS-RGC: CART, CDH6, FSTL4 | 80 days | NA | NA | NA |
Chen et al. [53] | 2019 | hiPSC | Neural spheres, RGC | RDM, RMM | IWR-1e, CHIR99021, SAG, N2, FBS, BDNF, RA, Y-27632 | RPC: VSX2(CHX10) RGC: MATH5(ATOH7), BRN3B, TAU, NFM | 34 days | NA | NA | NA |
Chavali et al. [54] | 2020 | hiPSC | RPC, RGC | RPC induction medium, RGC induction medium | B27, N2, nicotinamide, XAV939, SB431542, LDN193189, IGF-1, bFGF, SHH, SAG, FGF8, follistatin, cyclopamine, DAPT, Y-27632, forskolin, cAMP, BDNF, NT4, CNTF | RPC: SOX2, RAX, PAX6 RGC: THY1/CD90, TUJ1, MAP2, BRN3A, BRN3B, RBPMS | 36 days | Electro-physiological responses (patch-clamp recording) | 58% (THY1+) 84% (BRN3B+) 12% (RBPMS+) After MACS: 95% (BRN3A+) | Flow cytometry After MACS: ICC |
Rabesandratana et al. [55] | 2020 | hiPSC | Retinal organoid, RGC | Essential 6 medium, RDM | N2, B27, FGF2 | THY1, BRN3A, PAX6, HuC/D, βIII-tubulin, RBPMS | 63 days | Electro-physiological responses (patch-clamp recording, multi electrode array) | 78.03 ± 1.47% (THY1+) | Flow cytometry |
Gudiseva et al. [56] | 2021 | hiPSC | RPC, RGC | RPC induction medium, RGC induction medium | B27, N2, nicotinamide, XAV939, SB431542, LDN193189, IGF-1, bFGF, SHH, SAG, FGF8, follistatin, cyclopamine, DAPT, Y-27632, forskolin, cAMP, BDNF, NT4, CNTF | MAP2, RBPMS, TUJ1, BRN3A, SOX4, TUBB3 (βIII-tubulin), SNCG, PAX6, NRN1, CD90 (THY1) | 40 days | NA | 87% (BRN3+) 87% (SNCG+) 81% (THY1+) 19% (RBPMS+) | Flow cytometry |
Vrathasha et al. [57] | 2022 | hiPSC | RPC, RGC | RPC induction medium, RGC induction medium | B27, N2, nicotinamide, XAV939, SB431542, LDN193189, IGF-1, bFGF, SHH, SAG, FGF8, follistatin, cyclopamine, DAPT, Y-27632, forskolin, cAMP, BDNF, NT4, CNTF | RPC: Ki67, VSX2(CHX10) RGC: BRN3/POU4F, SNCG, THY1/CD90, RBPMS | 36 days | Electro-physiological responses (patch-clamp recording) | 87% (BRN3+) 93% (SNCG+) 85.5% (THY1+) 22.5% (RBPMS+) | Flow cytometry |
Luo et al. [58] | 2022 | hESC, hiPSC | RPC, RGC | RGC culture medium | B27, N2, FGF, insulin, sodium pyruvate, SATO supplement, L-glutamine, triiodothyronine, N-acetyl cysteine, BDNF, CNTF, forskolin, DAPT, GDNF | BRN3A, BRN3B, ISL1, SNCG, GAP43, ELAVL4 (HuD), ATOH7, RPBMS | 1 week | Electro-physiological responses (calcium imaging) | NA | NA |
Authors | Year | Cell Source | Differentiation Procedures | Differentiation Culture Media | Differentiation Factors | Immunostaining Markers | Time Length | Other Assays | Efficiency | Tests for Efficiency |
---|---|---|---|---|---|---|---|---|---|---|
Meyer et al. [19] | 2011 | hiPSC | Neural cluster, OV, photoreceptors | EB medium, NIM, RDM | Noggin, DKK1, N2, B27 | OTX2, RCVRN, CRX, NRL | 120 days | RT-qPCR, electro-physiological responses, calcium imaging | 55.9 ± 6.6% (CRX+) | ICC |
Zhong et al. [12] | 2014 | hiPSC | EF, NR, RC, photoreceptors | NIM | Heparin, N2, B27, taurine, RA | Precursor: OTX2, RCVRN Rod: RHO Cone: OPN1SW, OPN1L/MW | 21 weeks | light responsiveness (electrical recording) | 90% (RHO+) | IHC |
Barnea-Cramer et al. [95] | 2016 | hiPSC | EFP, RNP, eyecup, PhRP, photoreceptors | RIM, NDM | Noggin, N2, B27, insulin, BDNF, CNTF, RA, DAPT | Progenitor: CRX, NRL, NR2E3 Rod: RHO, RCVRN, PDE6α | 100 days | NA | NA | NA |
Zhu et al. [96] | 2018 | hiPSC | NR, RO, photoreceptors | MEM, NSC medium | Noggin, DKK1, N1, IGF-1, IWR-1, SB431542, LDN193189 | Precursor: OTX2, CRX, BLIMP1, AIPL1, RCVRN Rod: NRL Cone: THRB, ARR3, RXRγ | 70 days | RT-qPCR | 12 weeks: 52 ± 6% (OTX2+) 43 ± 3% (RCVRN+) | ICC |
Ovando-Roche et al. [97] | 2018 | hiPSC | NRV, photoreceptor | NIM (in bioreactor) | N2, B27, taurine, RA | Precursor: RCVRN Rod: RHO, CD133, CD73 Cone: OPN1SW, OPN1L/MW, ARR3 | 17 weeks | NA | 68.17 ± 6.15% (RCVRN+) 11.87 ± 1.88% (RCVRN+ CD73+) | flow cytometry |
Gagliardi et al. [98] | 2018 | hiPSC | NR, RO | Essential 6 medium, ProB27 medium | N2 supplement, FGF2 | Precursor: CRX, RCVRN, CD73 Rod: RHO Cone: OPN1SW, OPN1L/MW, ARR3 | 200 days | RT-qPCR, activity of CNG channels (calcium imaging) | 55 ± 2% (CD73+) | flow cytometry |
Li et al. [32] | 2018 | hiPSC | EB, NR, RO, photoreceptors | NIM, RDM | Heparin, N2, B27, taurine | Precursor: OTX2 Rod: RHO Cone: OPN1SW, OPN1L/MW | 9 weeks | NA | NA | NA |
Ribeiro et al. [99] | 2021 | hiPSC | RO, photoreceptors | Essential 6 medium, PIM, RDM | N2, B27, RA | Precursor: CRX, RCVRN Rod: RHO Cone: OPN1SW, OPN1L/MW | 90 days | Electro-physiological responses (multi-electrode array), quantitation of light responsiveness | 59 ± 3% (arrestin + OPN1L/MW+) | flow cytometry |
Sanjurjo-Soriano et al. [37] | 2022 | hiPSC | NR, RO, photoreceptors | Essential 6 medium, RDM | N2, B27, FGF2, taurine, RA | Precursor: CRX, RCVRN Rod: RHO, NRL, NR2E3 Cone: OPN1SW, OPN1L/MW, ARR3 | 225 days | Western blot (PDE6B expression) | 23.8–50.3% (ARR3+) 49.7–76.2% (RHO+) | IHC |
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Wong, N.K.; Yip, S.P.; Huang, C.-L. Establishing Functional Retina in a Dish: Progress and Promises of Induced Pluripotent Stem Cell-Based Retinal Neuron Differentiation. Int. J. Mol. Sci. 2023, 24, 13652. https://doi.org/10.3390/ijms241713652
Wong NK, Yip SP, Huang C-L. Establishing Functional Retina in a Dish: Progress and Promises of Induced Pluripotent Stem Cell-Based Retinal Neuron Differentiation. International Journal of Molecular Sciences. 2023; 24(17):13652. https://doi.org/10.3390/ijms241713652
Chicago/Turabian StyleWong, Nonthaphat Kent, Shea ** Yip, and Chien-Ling Huang. 2023. "Establishing Functional Retina in a Dish: Progress and Promises of Induced Pluripotent Stem Cell-Based Retinal Neuron Differentiation" International Journal of Molecular Sciences 24, no. 17: 13652. https://doi.org/10.3390/ijms241713652