Stem cell therapy in ocular pathologies in the past 20 years

Table 1 Clinical trials in ocular diseases

Ophthalmic disease	Ref.	Stem cells used	In animals or humans	Conclusions
Ocular surface, cornea and limbus	Kenyon and Tseng[52], 1989	Limbal tissue autograft transplantation (LSCs)	Humans	Patients have consistently shown improved visual acuity, rapid surface healing, stable epithelial adhesion without recurrent erosion, arrest or regression of corneal neovascularization
	Lindberg et al[53], 1993	LSCs	Humans	Corneal epithelial stem cells are located in the limbus and indicate that cultured autologous limbal cells may function as grafts to permanently restore the corneal epithelium after severe ocular surface injury
	Ma et al[54], 2006	MSCs like LSCs on amniotic membrane	Animals	Therapeutic effect due to the inhibition of inflammation and neovascularization
	Kwitko et al[57], 1995	Conjunctival autograft transplantation	Humans	Conjunctival transplantation proved to be an adequate method of treating severe bilateral surface disorders, with minimal complications
	Croasdale et al[58], 1999	Keratolimbal allograft	Humans	KLAL transplantation for patients with severe ocular-surface disease is an important management option
	Tsai et al[59], 2000	Limbal epithelial cells	Humans	By 1 mo, the ocular surface was covered with corneal epithelium, and the clarity of the cornea was improved in 83% of patients
	Sangwan et al[60], 2012	Limbal tissue	Humans	After surgery, a completely epithelialized, avascular and stable corneal surface was seen in all recipient eyes by 6 wk
	Kushnerev et al[61], 2016	Dental pulp stem cells	Animals	Dental pulp stem cells were successfully isolated, labeled, and delivered to the corneal surface
	Chan et al[66], 2013	iPSCs	Animals	hES cells can be induced to differentiate into keratocytes in vitro. Pluripotent stem cells may provide a renewable source of material for development of treatment of corneal stromal opacities
	Susaimanickam et al[67], 2017	iPSCs	Animals	PSC-derived corneal epithelial cells offer an alternative tissue source for regenerating different layers of the cornea and eliminate the need for complicated cell enrichment procedures
	Zeppier et al[3], 2017	MSCs	Animals	Better corneal repair in epithelium and stromal layers in stem cell treated eyes
	Reinshagen et al[68], 2011	BM-MSCs	Animals	BM-MSCs could differentiate into cornel epithelial like cells in vivo in rat damaged corneas
	Gu et al[70], 2009	BM-MSCs	Animals	BM-MSCs could differentiate into cornel epithelial like cells
	Beyazyildiz et al[46], 2014	MSCs	Animals	Topical application of MSCs could be a safe and effective method for the treatment of DES
	Reza et al[73], 2011	LSCs	Animals	Transplantation of a bioengineered CLEC-muc sheet in limbal stem cell-deficient rabbit eyes resulted in regeneration of a smooth, clear corneal surface
	Nishida et al[76], 2004	Oral mucosal stem cells	Humans	Complete reepithelialization of the corneal surfaces occurred within 1 wk in all four treated eyes. Corneal transparency was restored and postoperative visual acuity improved
Corneal stroma and endothelium	Sepsakos et al[79], 2017	Ocular surface SCs	Humans	Without addressing the underlying stem cell deficiency, keratoplasty in patients with total limbal stem cell deficiency will ultimately fail in all cases
	Naylor et al[81], 2016	iPSCs	Humans	The hiPSC-derived NCCs acquired a keratocyte-like morphology and an expression profile similar to corneal keratocytes in vivo
	Alió Del Barrio et al[84], 2017	ASCs	Humans	Safety of corneal stromal transplantation of autologous ASCs in humans, showing cell survival in vivo and the ability of these cells to produce a low amount of new collagen in patients with advanced keratoconus
	Coulson-Thomas et al[85], 2013	UC-MSCs	Animals	UC-MSCs transplantation may be a feasible alternative to keratoplasty in treating congenital disorders of the cornea secondary to keratocyte dysfunction
	Yam et al[88], 2018	Perodontal ligament SCs	Animals	Potential translation of PDL cells for regenerative corneal cell therapy for corneal opacities
	Joyce et al[89], 2012	UC-MSCs	Animals	UCB MSCs are able to "home" to areas of injured corneal endothelium and that the phenotype of UCB MSCs can be altered toward that of HCEC-like cells
Trabecular meshwork	Abu-Hassan et al[93], 2015	iPSCs	Animals	TM-like iPSCs became similar to TM cells in both morphology and expression patterns. When transplanted, they were able to fully restore intraocular pressure homeostatic function
	Manuguerra-Gagné et al[95], 2013	MSCs	Animals	MSC and their secreted factors induced reactivation of a progenitor cell pool found in the ciliary body and increased cellular proliferation
Lens	Lin et al[96], 2016	LECs	Both	Surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts
	Murphy et al[98], 2018	PSCs	Animals	We demonstrate large-scale production of light-focusing human micro-lenses from spheroidal masses of human lens epithelial cells purified from differentiating pluripotent stem cells
ON	Kuwahara et al[102], 2015	hESCs	Animals	Multipotent stem cells within the CM contribute to de novo retinal tissue growth
	Mesentier-Louro et al[105], 2019	iPSCs	Animals	Between 1% and 7% of iPSCs-derived RGCs integrated into the ganglion cell layer after intravitreal injection, and about 20% after combined injection of RGCs and iPSCs
	Zhang et al[107], 2015	UC-MSCs	Animals	Human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, improve biomechanical properties, and contribute to the recovery after injury

ASC: Adipose-derived stem cell; BM-MSC: Bone marrow-mesenchymal stem cell; CLEs: Cutaneous lupus erythematosus; CM: Ciliary margin; DES: Discrete event simulation; HCEC: Human corneal endothelial cell; hESCs: Human embryonic stem cells; hiPSC: Human-induced pluripotent stem cells; iPSC: induced pluripotent stem cell; KLAL: Keratolimbal allograft; LEC: Lens epithelial stem/progenitor cell; LSC: Limbal stem cell; MSC: Mesenchymal stem cell; NCC: Neurocysticercosis; ON: Optic nerve; PDL: Periodontal ligament; PSC: Pluripotent stem cell; RGC: Retinal ganglion cell; TM: Trabecular meshwork; UC-MSCs: Umbilical cord-mesenchymal stem cell; UCB: Umbilical cord blood.

Table 2 Retinal diseases and therapies

Ophthalmic disease	Ref.	Stem cells used	In animals or in humans	Conclusions
Retina	Van Meurs et al[109], 2004	RPE cells	Humans	A pigmented area was seen in the extraction bed of the neovascular membrane in only one patient
	Tucker et al[110], 2011	iPSCs	Animals	Adult fibroblast-derived iPSCs provide a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease
	Lamba et al[111], 2006	hESCs	Animals	hES cell derived retinal progenitors integrate with the degenerated mouse retina and increase in their expression of photoreceptor-specific markers
	Nakano et al[48], 2012	IPSCs/hESCs	Humans	We demonstrate that an optic cup structure can form by self-organization in hESC culture
	Gonzalez-Cordero et al[113], 2013	ESCs	Animals	We show that rod precursors integrate within degenerate retinas of adult mice and mature into outer segment-bearing photoreceptors
	Schwartz et al[40], 2015	hESCs	Humans	First evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with macular diseases
	Schwartz et al[114], 2012	hESCs	Humans	The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 mo
	Gaddam et al[120], 2019	Adult stem cells	Humans	The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue

hESCs: Human embryonic stem cells; iPSC: induced pluripotent stem cell; RPE: Retinal pigment epithelium.