Table 2 Differentiation methods of human stem cells toward photoreceptors

Human fetal neural stem cells (fNSC)

Direct differentiation

TGF-β3

Photoreceptors,

OPSIN (D15)

The transplanted cells in the rat model showed the extensive migration into the lesion area of the retina [460]

Human exfoliated deciduous teeth (SHEDs)

Direct differentiation

N2,B27, FGF2, noggin, Dkk1, IGF-1, Shh, T3, RA

Photoreceptors,

RECOVERIN, CRX, NRL (D24)

Injected SHEDs into the mouse eyes could differentiate into rod- and cone-like cells; retinal function improved, and photoreceptors were rescued for 3–5 months [468]

hBM-MSC

Spontaneous differentiation, Direct differentiation

FGF2, EGF, BDNF

Photoreceptors,

RHODOPSIN (D7)

Phase I trial was done in 3 patients with RP and two patients with cone-rod dystrophy 10 months after transplantation revealed no detectable structural or functional toxicity, demonstrating the short-term safety of the transplantation (NCT01068561) [492]. Phase II study enrolled 20 RD patients. Findings showed vision-related life quality improvement 3 months post treatment (NCT01560715) [493]

hRSCs

Direct differentiation

FGF2, EGF

Rod photoreceptors,

RHODOPSIN (D21)

After transplantation into the mouse eye, the cells showed photoreceptor morphology and expressed RHO marker; also able to integrate into different neuronal layers at appropriate developmental times [470]

hRPCs

Direct differentiation

N2, B27, FGF2, EGF

Photoreceptors,

RHODOPSIN and

RECOVERIN (D14)

Transplantation in RCS rats revealed the integration and expression of specific markers. Also clinical study in retinitis pigmentosa 8 patients after 1–2 years post-transplantation clarified no obvious autofluorescence destruction in the macular area and also significant improvement in visual acuity. Although poor visual function of the patients prior to the study was detected. No immunological rejection was not observed after transplantation in both animal study and clinical trial [466, 494, 495]

hESCs

Direct differentiation

N2, B27, FGF2, IGF-1, Dkk1, Noggin, COCO

Con Photoreceptors,

CRX, S-OPSIN (D21)

Injected cell clamps into the vitreous of neonatal (P1) mice were presented in the PR nuclear layer by expression of S-opsin and the same morphology of host PRs [496]

hiPSCs

Direct differentiation

N2, B27, IGF-1, Dkk1, Noggin, DAPT, FGF1 and 2

Rod Photoreceptors,

RECOVERIN (D90) and RHODOPSIN (D120)

Two weeks following transplantation into neonatal retinal degenerative Crb1 mutant mice, PR precursor cells were integrated into the outer nuclear layer and differentiated into morphologically and immunohistochemically recognizable PRs [497]

hESCs/hiPSCs

Direct differentiation

N2, B27, Noggin, BDNF, CTNF, Insulin, DAPT, RA

Photoreceptors,

CRX, NRL, NR2E3 (D90-100)

Three weeks post transplantation in the adult rd1 eye, the expression of mature PR markers and functional analysis indicated visual improvement [489]

hESCs/ hiPSCs

Direct differentiation

N2, B27, FGF2, IGF-1, Dkk1, Noggin

Photoreceptors,

CRX, NRL (120) RECOVERIN, RHODOPSIN, S-OPSIN (60)

After transplantation to the sub-retinal space, the cells begin to move into the retina and expresses mature PR markers [454, 455]

hESCs/ RPE

Co-culture differentiation

N2, B27, FGF2, IGF-1, Dkk1, Noggin, Shh

Photoreceptors,

RHODOPSIN, S-OPSIN (D40-50)

Following transplantation of Shh-treated retinal cells in eighteen adult albino rabbits for 4 weeks showed ERG improvement, and also cell incorporation into the retina, and finally visual restoration [491]