Table 2.
Summary of differentiation and transplantation studies of hiPSCs
| Reference | Differentiation condition | In vitro Characteristics | In vivo Characteristics | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Cell line | Early stage | Maturation stage |
Cell fate | Functional analysis |
Animal model |
Graft innervation |
TH+ neuron count/graft |
Behavior improvement |
|
| Chambers et al. (2009) | iPSC14, iPSC27 | Noggin, SB B, AA, SHH, FGF8 |
B, AA, G, T, C | TH+/Tuj1+ staining | N/A | N/A | N/A | N/A | N/A |
| Swistowski et al. (2010) | MR31, MMW2 | EB, SHH, FGF8 | B, AA, G, T, C | TH+ (30±5%) | N/A | 6-OHDA rat | N/A | 2,106±313/mm3 | AMP-IR |
| Cai et al. (2010) | IMR90-4 | EB, N2, B27 bFGF |
N2, B27, C | TH+ (6.5±1.4%) | DA release | 6-OHDA rat | N/A | N/A | No improvement |
| Hargus et al (2010) | A6, K1, S1, FF 17-5, FF 21-26 | Noggin, N2, SHH, FGF8, B, AA | B, AA, G, T, C | TH+ (3~9%) TH+/Tuj1+ (15~35%) |
N/A | 6-OHDA rat | Grafts send projections to the surrounding gray and white matter | 4,890±640 | AMP-IR |
| Kriks et al. (2011) | 2C6, SeV6 | LDN, SB, SHH, FGF8, PMN, CHIR | B, AA, G, T, C, D | TH+ (70%) TH+/FOXA2+ (15~20%) |
DA release Electrophysiology | 6-OHDA mouse 6-OHDA rat MPTP monkey |
hNCAM+ fibers extended to the non-transplanted brain side | >15,000 | AMP-IR, cylinder test, stepping test |
| Kikuchi et al. (2011) | 253G4 | DM, SB FGF8, SHH |
B, AA, G, C | TH+/Tuj1+ (85.46±3.13%) | DA release | MPTP monkey | N/A | 3.07×104 ~ 1.26×105 | Neurological score, time in movement |
| Morizane et al. (2011) | 201B6, 201B7, 253G1, 253G4 | SB, DM, PMN FGF8 |
B, AA, G, C | TH+/Tuj1+ Staining | N/A | N/A | N/A | N/A | N/A |
| Rhee et al. (2011) | IMR90-1, IMR90-4 Foreskin-1, SES8 Rv-hiPS |
EB, ITSA, bFGF, SHH, FGF8 | B, G, C | TH+/Tuj1+ (35~45%) | Electrophysiology DA release | 6-OHDA rat | N/A | 26,882±9089~54,418±23,660 | APO-IR |
| Jiang et al. (2012) | C001, C002, P001, P002 | B27, SB, bFGF, FGF8, SHH, AA, Wnt3a | FGF8, SHH, B, AA, G, T, C | TH+/FOXA2+ staining | Electrophysiology DA release | N/A | N/A | N/A | N/A |
| Sánchez-Danes et al. (2012) | Normal iPSC; PD iPSC; LRRK2 PD iPSC | EB, FGF2, N2/B27, FGF8, SHH | Co-culture with PA6, N2/B27 FGF8 and SHH | TH+/Tuj1+ (50~60%) | Electrophysiology DA release | N/A | N/A | N/A | N/A |
| Xi et al (2012) | IMR90-4 | SB, LDN, SHH, CHIR, FGF8b | B, AA, G, T, C | FOXA2+/TH+ (>90%) | Electrophysiology | N/A | N/A | N/A | N/A |
| Sundberg et al. (2013) | 2135 and 1815 | SB, LDN, SHH, PMN, FGF8a, CHIR, Noggin, SAG, Wnt1, RA | B, AA, G, C, D | TH+ (>10~20%) | N/A | N/A | N/A | N/A | N/A |
| Zhang et al. (2014) | Normal iPSC; PD iPSC | SB, LDN, SAG, FGF8b, PMN, CHIR | B, AA, G, T, C | TH+ staining | N/A | N/A | N/A | N/A | N/A |
| Doi et al. (2014) | 404C2, 836B3 | LDN, A83-01, PMN, FGF8, CHIR | B, AA, G, C | TH+ (20~45%) | DA release | 6-OHDA rat | N/A | 1,900±658 ~ 6,747±2,341 | AMP-IR |
| Han et al. (2015) | NCF-1, NCF-2, NCF-3, PD-1, PD-2 | Noggin, SB, SHH, B, A, FGF8 | B, AA, G, T, C | TH+ (33%) | N/A | 6-OHDA rat | N/A | N/A | APO-IR, rota-rod test |
| Komatsu et al. (2015) | 201B7, 253G1 | EB, SB, LDN, SHH, FGF8, PMN, CHIR | B, AA, G, T, C | TH+ (63±13%) | DA release | N/A | N/A | N/A | N/A |
| Effenberg et al. (2015) | hCBiPSCs | EB, FGF2, SHH, DM, SB, PMN, FGF8 | B, AA, G, T, C | TH+ (3.5~7.4%) | N/A | 6-OHDA rat | TH+ fiber outgrowth inside the grafts | 1,800±1,506 ~ 10,034±5,654 | N/A |
| Samata et al. (2016) | 1039A1 | A83-01, LDN, FGF8, PMN, CHIR | B, AA, G, C | TH+/FOXA2+ (>30%) after LRTM1+ sorting | DA release Electrophysiology | 6-OHDA rat | N/A | 44,777±72,03 | APO-IR, AMP-IR |
| MPTP monkey | Graft extended TH+ fibers into host brain | ~ 2.4 × 105 | N/A | ||||||
| Kikuchi et al. (2017a) | Normal iPSC PD iPSC |
A83-01, LDN, FGF8, PMN, CHIR | B, AA, G, C | FOXA2+/Tuj1+ (87.5±2.6%) Nurr1+ (16.4±3.8%) |
Electrophysiology | MPTP monkey | Graft extended TH+ fibers into host brain | 6.4±4.9 × 104 | Neurological score |
| Kikuchi et al. (2017b) | Normal iPSC PD iPSC |
A83-01, LDN, FGF8, PMN, CHIR | B, AA, G, C | FOXA2+ (95.3±1.6%) Nurr1+ (17.8±2.4%) |
Electrophysiology | 6-OHDA rat | Graft extended TH+ fibers into host brain | 227±94 ~ 267±51 | AMP-IR |
| Lehnen et al. (2017) | hFF-iPSC | EB, SB, LDN, CHIR, SHH, PMN | B, AA, G, C or D | FOXA2+>90% after IAP sorting | N/A | 6-OHDA rat | Graft extended TH+ fibers into host brain | 840~5200 | AMP-IR |
Abbreviations: AA, Ascorbic acid; AMP-IR, Amphetamine-induced rotation; APO-IR, Apomorphine-induced rotation; B, BDNF; C, Dibutyryl cAMP; C-E, Compound E; CHIR, CHIR99021; D, DAPT; DM, Dorsomorphin; EB, Embryoid body; G, GDNF; hNCAM, Human neural cell adhesion molecule; ITSA, Insulin-Transferrin-Selenium-Sodium Pyruvate; LDN, LDN193189; N/A, Not available; PMN, Purmorphamine; SAG, Smo agonist; SB, SB431542; SHH, Sonic Hedgehog; T, TGF-β3