Table 1.

Manipulation of different type of extraocular stem cells for treating ocular disorders in preclinical and clinical trials.

Stem cells	Experimental design/research or disease model	Route of injection	Research outcomes	References/sources
Hematopoietic stem cells (HSCs)	Chemically damaged retinal neuron in mice	Intravenous injection	Fusion with ganglion, amacrine, and Müller glial cells, heterokaryons reprogramming, and dedifferentiation into neuroectodermal lineage	Sanges et al. [82]
	Delivery of granulocyte-colony stimulating factor in rats with retina ischemia	Intravenous injection	Apoptosis of retinal cells was reduced and improved visual function Localization of HSCs in the retinal layer	Lin et al. [94]
	Transplantation of human HSCs in mice with acute retinal ischemia-reperfusion injury	Intravenous injection	HSC-treated group of mice showed improved retinal histopathology. However there was no significant difference compared to control mice. No intraocular tumor and no abnormal proliferation of human cells in major organs	Park et al. [83]
	Transplantation in retinal degenerative conditions (atrophic ARMD, Retinitis Pigmentosa) or retinal vascular disease (diabetes, vein occlusion)	Intravitreal injection	Clinical trial to measure primary outcome on adverse events is still ongoing	NCT01736059 (ClinicalTrials.gov)
Induced pluripotent stem cells (iPSCs)	Injection of mouse fibroblast iPSC-conditioned medium	Intravenous injection	Maintenance of retina integrity and function by reducing apoptosis of retinal neurons following photodamage	Chang et al. [91]
	Swine iPSCs-derived photoreceptors	Subretinal injection	Integration of photoreceptors was observed in chemically damaged retina	Zhou et al. [90]
	Generation of 3-dimensional neural retina sheet derived from mouse iPSCs and ESCs for subretinal transplantation into retinal degenerative mice	Subretinal injection	Development into outer nuclear layer (ONL) with completely structured inner and outer segments of photoreceptor	Assawachananont et al. [95]
	Generation of photoreceptor cell from adult mouse dermal fibroblast-derived iPSCs for subretinal transplantation into retinal degenerative mice	Subretinal injection	Development of functional photoreceptor in mice	Tucker et al. [96]
	Generation of RPE sheets from human iPSCs for transplantation into wet ARMD patients	Submacular injection	Pilot safety study involving six patients is currently ongoing. RPE were observed to be retained in patients	Kamao et al. [141]
Embryonic stem cells (ESCs)	In vitro differentiation of rostral neural progenitors into retinal neuron cells	Not available	Increased cell expression of CRX, S-opsin, and Rho/Rcvrn in hypoxic culture condition, indicating differentiation	Garita-Hernández et al. [93]
	Treatment of patients affected by Stargardt's macular dystrophy and atrophic ARMD with human ESCs-derived RPE suspension	Submacular injection	Improved visual function. No signs of hyperproliferation, tumorigenicity, ectopic tissue formation, and immune rejection were observed	NCT01344993, NCT01345006  (ClinicalTrials.gov)
	Treatment of patients affected by wet ARMD with human ESCs-derived RPE sheets	Intraocular injection	Clinical trial is still ongoing. This method of delivery is hoped to overcome the disadvantages of using ESC-derived RPE suspension	NCT01691261  (ClinicalTrials.gov)
Mesenchymal stem cells (MSCs)	Injection of bone marrow-derived MSCs into a laser-induced ocular hypertensive glaucoma of rat model	Intravitreal injection	Increase in retina ganglion cell (RGC) axon survival and significant decrease in the rate of RGC axon loss normalized to cumulative intraocular pressure exposure	Johnson et al. [97]
	Transplantation of bone marrow-derived MSCs into Retinopathy of Prematurity (ROP) rat model	Not available	Reduced apoptosis in retinal cells with higher expression of neurotrophin-3 and CNTF in ROP rats	Zhao et al. [86]
	Direct topical application of MSCs or MSCs-conditioned medium on cornea for two hours	Corneal surface	Reduced inflammation, opacity, and neovascularization in chemically burned cornea	Oh et al. [85]
	Transplantation of bone marrow-derived MSCs in rats following optic nerve crush	Intravitreal injection	Rescued degeneration of retinal ganglion cells and axon regeneration	Mesentier-Louro et al. [88]
	Transplantation of bone marrow-derived MSCs in alkali-induced oxidative stress rabbit corneas	Corneal surface	Reduced apoptosis in corneal epithelial cells, vascularization, and infiltration of macrophages	Cejkova et al. [87]
	In vitro differentiation of adult human bone marrow stem cells with retinal pigmented epithelium cells	Coculture experiment	Differentiated cells expressed neuronal and photoreceptor phenotypes	Chiou et al. [98]
	Transplantation of MSCs overexpressing pigment epithelium derived factor in animal models of choroid neovascularization	Not available	Inhibition of neovascularization and MSCs adopted RPE phenotypes	Liu et al. [76]
	Delivery of human adipose-derived MSCs to light-induced in vitro and in vivo models	Intravitreal injection	Inhibition of photoreceptor degeneration and retinal dysfunction	Sugitani et al. [99]
	Transplantation of human umbilical cord blood-derived MSCs to neurodegenerative rat model	Intraperitoneal injection	Promotion of regeneration and protection of damaged retinal ganglion cells	Zwart et al. [166]
	In vivo delivery of human umbilical cord-derived MSCs to early retinal degenerative rat model	Subretinal injection	Preservation and rescue of photoreceptor degeneration and improvement in visual functions	Lund et al. [167]
	Delivery of ADSCs into atrophic ARMD patients. The cells are harvested from liposuction tissues	Intravitreal injection	Clinical trial to measure primary outcomes on adverse events; visual acuity and visual field analysis is still ongoing	NCT02024269  (ClinicalTrials.gov)
Adipose-derived stem cells (ADSCs)	Injection of BMSCs in patients with advanced ARMD (atrophic or neovascular)	Intravitreal injection	Clinical trial to measure primary outcome on visual acuity is still ongoing	NCT01518127  (ClinicalTrials.gov)
Bone marrow stem cells (BMSCs)	Unilateral ocular transplantation into patients with advanced atrophic AMD	Subretinal injection	Clinical trial to measure primary outcome on adverse events is still ongoing	NCT01632527  (ClinicalTrials.gov)
Central nervous system stem cells (hCNS-SCs)	Unilateral ocular transplantation into patients with advanced atrophic AMD	Subretinal injection	Clinical trial to measure primary outcome on adverse events is still ongoing	NCT01632527  (ClinicalTrials.gov)