Zhang C-J and Jin Z-B, J Stem Cell Res Dev 2019, 5: 014

DOI: 10.24966/SRDT-2060/100014

HSOA Journal of
Stem Cells Research, Development and Therapy
Review Article

BM: Bruch’s Membrane;

Restoring Vision with RPE: Retinal Pigment Epithelium;
Photoreceptor Regeneration STGD: Stargardt’s Disease
RPCs: Retinal Progenitor Cells
hRPCs: human-derived RPC
Chang-Jun Zhang1,2 and Zi-Bing Jin1,2*
MG: Müller Glia
Laboratory for Stem Cell & Retinal Regeneration, Institute of Stem Cell
1
NMDA: N-methyl-D-aspartate
Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou
CE: Ciliary Epithelium
Medical University, Wenzhou 325027, China
IPE: Iris Pigmented Epithelium
2
State Key Laboratory of Ophthalmology, Optometry and Vision Science,
ESCs: Embryonic Stem Cells
National Clinical Research Center for Ophthalmology, National Center
for International Research in Regenerative Medicine and Neurogenetics, iPSCs: Induced Pluripotent Stem Cells
Wenzhou 325027, China hiESCs: human ESCs
hiPSCs: human iPSCs
MSCs: Mesenchymal Stem Cells
Abstract ADSCs: Adipose-Derived Stem Cells
Neuroretinal diseases are the predominant cause of irreversible
AESCs: Amniotic Epithelial Stem Cells
blindness worldwide, mainly due to photoreceptor loss. Currently, BMSCs: Bone Marrow Mesenchymal Stem Cells
there are no radical treatments to fully reverse the degeneration AFMSCs: Amniotic Fluid Mesenchymal Stem Cells
or even stop the disease progression. Thus, it is urgent to develop 2D: Two-Dimensional
new biological therapeutics for these diseases on the clinical side.
Stem cell-based treatments have become a promising therapeutic
3D: Three-Dimensional
for Neuroretinal diseases through replacement of damaged cells LIF: Leukemia Inhibiting Factor
with photoreceptors and allied cells. To date, great efforts have been BMP: Bone Morphogenetic Protein
made on regenerate the diseased retina based on stem cell technol- IGF-1: Insulin-Like Growth Factor-1
ogy. In this review, we overview the current status of stem cell-based
treatments for photoreceptor regeneration, including the major cell
SFEB: Serum-Free Floating Culture System
sources derived from different stem cells in pre-clinical or clinical trial ERG: Electroretinogram
stages. Additionally, we discuss herein the major challenges ahead FACS: Fluorescence Activated Cell Sorting
for and potential new strategy toward photoreceptor regeneration. MACS: Magnetic Activated Cell Sorting
Keywords: Delivery strategy; Neuroretinal diseases; Photoreceptor; INL: Inner Retinal Layer
Regeneration; Stem cell ECM: Extracellular Matrix
OKT: Optokinetic Testing
Abbreviations SD-OCT: Spectral Domain-Optical Coherence Tomography
HAMC: Hyaluronan-Methylcellulose
QOL: Quality of Life HLAs: Human Leukocyte Antigens
CNS: Central Nerve System RA: Retinoic Acid
RD: Retinal Degeneration LCA: Leber Congenital Amaurosis
RP: Retinitis Pigmentosa GVHD: Graft Versus Host Disease
AMD: Age Related Macular Degeneration CSNB: Congenital Stationary Night Blindness
*Corresponding author: Zi-Bing Jin, Laboratory for Stem Cell & Retinal Regen-
eration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Introduction
Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China, Tel: +86
57788067926; E-mail: jinzb@mail.eye.ac.cn Human eye, the organ of the visual system, is the most important
Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Re- organ of perception and converts visual signals into neural signals
generation. Stem Cell Res Dev Ther 4: 014. in the brain [1,2]. The structure of the human eye is incredibly com-
plex, comprising the cornea, iris and lens from the anterior segment,
Received: July 29, 2019; Accepted: August 12, 2019; Published: August 19, and the vitreous humor, retina, choroid and sclera from the posterior
2019
segment [3,4]. Healthy and asymptomatic eyes are undoubtedly cru-
Copyright: © 2019 Zhang C-J and Jin Z-B. This is an open-access article dis- cial to Quality of Life (QOL). Unfortunately, there are many differ-
tributed under the terms of the Creative Commons Attribution License, which ent diseases and age-related changes that affecting the eye, ranging
permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited. from the anterior segment to the posterior segment [5,6]. Apart from
Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
neuroretinal disorders, a good therapeutic effect can be achieved in
most eye diseases in the anterior segment with current medical treat-
ments.
The retina is a part of the Central Nerve System (CNS) and is pri-
marily composed of seven cell types [7-9]. In the mammalian retina,
three vital cell types, including photoreceptors, Retinal Pigment Epi-
thelium (RPE) cells and retinal ganglion cells, lack self-regenerative
capacity after injury. Thus, neuroretinal disorders, such as Retinal De-
generation (RD) and glaucoma, can lead to irreversible and incurable
visual impairment with the loss of photoreceptors, RPE cells, and/or
retinal ganglion cells [10].
Retinal degeneration (RD) encompasses a group of major regis-
tered blindness-causing diseases accompanied by the death of pho-
toreceptors and/or RPE cells that result in progressive loss of vision
and severely impact the quality of patient’s life [11-14]. RD primarily
includes Retinitis Pigmentosa (RP) and macular degeneration, which
has a high clinical incidence, and these diseases exhibit different
symptoms and result from complex disease-causing factors. RP is an
inherited retinal disorder involving more than 90 causal genes, and
typical symptoms include progressive night blindness and loss of pe-
ripheral visual field [15-17]. RP affects more than 1.5 million individ-
uals worldwide with a prevalence rate of approximately 1 in 4000 [15,
18].
Different from inherited and rod-dominated RP, macular degen-
eration is an over determined and cone-dominated disease caused by
both innate and acquired factors and mainly includes Age-Related
Macular Degeneration (AMD) and juvenile macular degeneration
[19,20]. The thickened Bruch’s Membrane (BM) is the initial charac-
terization of AMD, and subsequently, the loss of RPE cells and photo-
receptors gradually occurs in the late stage [21-26]. It is estimated that
the number of AMD cases will reach nearly 196 million worldwide
by 2020 and 288 million by 2040, leading to an increased social and
economic burden [27-29]. Stargardt’s Disease (STGD) is the highest
prevalence of juvenile macular degeneration [30-33]. Both diseases
are currently incurable in terms of photoreceptor maintanance and
disease reversion.
As seen from the foregoing descriptions, traditional therapeutic
approaches for neuroretinal diseases can only delay the progression
of neuroretinal degeneration and are unable to cure or completely re-
verse the damage caused by the disease. Unlike the retina in lower
vertebrates, the human retina lacks a regenerative capability [34,35].
Stem cells are special cell types characterized by the capacity of un-
limited self-renew and the ability of multidirectional differentiation
into multiple cell types, including photoreceptors, RPE cells, and/or
retinal ganglion cells [36]. In recent years, based on these character-
istics of stem cells, stem cell transplantation has been well studied
and widely used as a feasible approach for maintaining, enhancing
and restoring the function and structure of tissues or organs [37]. In
particular, the eye has some natural advantages over other tissues and
organs in the field of stem cell transplantation therapy; first, the rela-
tively small size only requires a small volume of cells for transplan-
tation; second, because the eye is easily accessible and observable
highly invasive methods for surgery or examination can be avoided;
third, the immune privileged sites can help to prevent unwanted in-
flammatory responses and thus promote the survival of donor cells;
fourth, the comparatively independent, separated space can minimize
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systemic dissemination and maintain the intraocular microenviron-
ment; last, the highly sectionalized structure can permit specific tar-
geted interventions for different ocular tissues [38-41]. During the last
two decades, stem cell-based therapy for neuroretinal diseases have
become a promising treatment strategy due to the continued advanc-
es in generation of appropriate cell sources, development of optimal
delivery systems, and exploration of combined cell transplantation.
Stem Cells for Regeneration of the Retina
The primary problem facing stem cell transplantation for neuroret-
inal diseases is identification and characterization of the source of
stem cells. Accessible and efficient stem cell sources for neuroretina
regeneration are classified into two main categories, endogenous reti-
nal stem cells and exogenous stem cells for retinal regeneration.
Endogenous Retinal Stem Cells
The study of restoring vision through retinal transplantation can
be traced back to the 1950s, when a donor fetal mouse retina was
transplanted into an adult mouse with incomplete integration into the
host retina [42]. Subsequently, further studies found that transplanta-
tion integration could be increased when the donor or host tissue is at
an early stage or the host retina is injured.
Retinal Progenitor Cells (RPCs) have been identified as the ef-
fective cellular component of fetal or neonatal retinal transplantation
[43-45]; transplantation of isolated RPCs promotes integration with
the host retina [46,47]. RPCs have a multipotential differentiation
capacity, exhibit expression of the neuroectodermal marker nest in
and can potentially differentiate into all retinal cells (e.g., Müller glial
cells, rod photoreceptors and bipolar neurons) during development
[48,49]. In the early stage of mammal retinal development, RPCs, as
the predominant cell type, are easy to isolate from several mammalian
species, including rodents, pigs, and humans [50-52]. Surprisingly,
in addition to cells from fetal or neonatal epiretinal membrane in the
adult human retinas, suggesting that the mature retina may harbor
RPCs [53,54]. Mouse-, rat-, cat-, and pig-derived RPCs, as well as
human-derived RPCs (hRPCs), have been applied to replace damaged
cells in corresponding animal disease models with good differentia-
tion and integration [46,55-59]. However, the low rate of RPC cell
proliferation and ethical issues regarding clinical application of RPCs
harvested from fetal or neonatal eyes limit their transplantation into
human patients.
For the treatment of retinal degenerative diseases, in addition to
attempts to replace damaged cells through stem cell transplantation,
the endogenous ocular stem cell populations can be reactivated to
generate new retinal photoreceptors [60-62]. The well-known endog-
enous retinal stem cells Müller Glia (MG) are derived from the retinal
neuroepithelium and are the major glial unable to the retina [63,64].
MG span the entire length of this structure and function to maintain
retinal homeostasis and integrity [65]. Unlike most cell types, the dif-
ferentiated retinal neurons are incompetent to divide and regenerate
once damaged or lost. Surprisingly, MG has a prominent ability to
regenerate retinal tissue; however, the capacity for MG regeneration
varies greatly among different species. In some non-mammalian spe-
cies, such as chick, fish and birds, MG have an ability to regenerate
neurons [66-68]. In zebrafish, MG generate various retinal neurons
and restore visual function through a reprogramming event. In con-
trast to zebrafish, mammalian MG encounter reactive gliosis and
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Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
exhibit hypertrophy after retinal impairment but fail to regenerate nov-
el neurons to replace lost cells under natural circumstances [69]. Spe-
cially, mammalian MG can also proliferate and regenerate the adult
mammalian retina in response to N-methyl-D-aspartate (NMDA)
neurotoxicity in the adult rat retina [70,71]. Further studies showed
that the mammalian retina is also capable of regenerating inner retinal
neurons after treatment with specific growth factors in mouse retina
with intraocular NMDA [72]. Likewise, following NMDA injection
in rats, MG started to proliferate mediated by cyclin D1- and D3- re-
lated pathways and differentiated exclusively into rhodopsin-positive
cells surrounded by synaptophysin, showing the potential for synapse
formation [73]. In addition to these neurotoxic substances, axotomy
and laser injury can also result in proliferation and differentiation
of MG into retinal neurons in vivo [74,75]. Furthermore, molecular
fingerprinting showed that MG express genes associated with retinal
stem cells in the mouse retina [76].
Although the differentiation potential of endogenous human MG
has not yet been shown, in vitro, MG isolated from adult human ret-
inas was shown to possess an ability to differentiate into rod photo-
receptors for the first time [77]. Moreover, human MG-derived pho-
toreceptors and MG-derived retinal ganglion cells were transplanted
into deficient rodent retinas, resulting in the functional restoration of
rod or retinal ganglion cells [78-80]. Although some previous stud-
ies have shown that the newly generated neurons are functional and
can partially restore visual function, neurogenesis is still limited, evi-
denced by the low number of regenerated cells. Thus, novel strategies
are required to maintain adequate numbers of MG and promote their
effective trans-differentiation to regenerate newly formed retinal neu-
rons in vivo.
As with MG, many previous studies showed that some other oc-
ular stem cells, including RPE [81,82], the Ciliary Epithelium (CE)
[83,84], and Iris Pigmented Epithelium (IPE) [85-87], also retain
some restricted regenerative capacities. However, the efficiency of
reprogramming and the potential of produced new cells derived from
these endogenous stem cells are so low that they do not achieve ex-
tensive replacement of mature mammalian eyes after injury or dis-
ease. Based on the advancement of in vitro culture techniques, they
may also be promising as a source of donor cells for cell replacement
therapy. Moreover, the development of new techniques to induce
reactivation and differentiation of endogenous stem cells is another
breakthrough in the treatment of neuroretinal diseases.
Exogenous Stem Cells
Exogenous stem cells for retinal regeneration are primarily
non-ocular stem cells. The non-ocular stem cells that can generate ret-
inal cells are mainly divided into three types, Embryonic Stem Cells
(ESCs) [88], induced Pluripotent Stem Cells (iPSCs) induced from
mature somatic cells [89], and Mesenchymal Stem Cells (MSCs)
[90]. MSCs can be obtained from various sources, including Adi-
pose-Derived Stem Cells (ADSCs) [91], Amniotic Epithelial Stem
Cells (AESCs) [92], Bone Marrow Mesenchymal Stem Cells (BM-
SCs) [93], and Amniotic Fluid Mesenchymal Stem Cells (AFMSCs)
[94]. ESCs and iPSCs are currently widely used and have been se-
lected as prospective therapeutic strategies for neuroretinal diseases;
thus, they are our next narrative focus.
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Differentiation of ESCs and iPSCs into Photorecep-
tors and RPE Cells
The first pluripotential cells from mouse embryos were established
by Martin, Evans and Kaufman in 1981 [95]. Subsequently, Tomson
and colleagues isolated ESCs from primate and human embryos in
1998 [88]. ESCs and iPSCs are capable of differentiation into various
retinal cell types using Two-Dimensional (2D) or Three-Dimension-
al (3D) culture systems, including photoreceptors [96,97], RPE cells
[98,99], and retinal ganglion cells [97,100].
Deriving Photoreceptors from ESCs and iPSCs
Direct differentiation of ESCs into neural and retinal cell types can
be guided by manipulation of signaling pathways in vivo, sequentially
followed by the withdrawal of Wnt signaling, Leukemia Inhibiting
Factor (LIF), and Bone Morphogenetic Protein (BMP) and the acti-
vation of Insulin-Like Growth Factor 1 (IGF-1) and Activin/Nodal
signaling pathways [96,101-109]. Mouse ESC-derived neuroretinal
cells have been induced in vivo by using certain factors for neural and
retinal induction [106]. Mouse ESCs successfully generated retinal
progenitors in the presence of FBS at reasonable efficiency (26%)
after treatment in A Serum-Free Floating Culture System (SFEB) with
addition of Dkk1 (a Wnt antagonist), Lefty A (a nodal antagonist),
serum and activin, successively. However, only in co-culture with
embryonic retinal cells can these retinal progenitors efficiently differ-
entiate into photoreceptor precursors [106,110]. Subsequently, human
ESCs were reported to produce neural progenitors in vitro, but their
differentiation into retinal cells needs to be performed via intraocular
transplantation into adult rats [111]. Similarly, human ESC-derived
retinal progenitors were induced under the addition of dkk1, noggin
and IGF-1 in Matrigel and continued to generate photoreceptors in
co-culture with adult mouse retinal cells [112]. A groundbreaking
work showed that mouse, monkey and human ESC-derived photore-
ceptor precursors was realized under optimized culture conditions in
vitro, with elimination of the need for animal-derived substances or
retinal tissue [113].
Ethical issues and immune rejection are major constraints in clini-
cal application of hESCs [114]. In 2006 and 2007, mouse and human
somatic cells were induced for the first time to form the pluripotent
stem cells via reprogramming using the “Yamanaka factors”, Oct3/4,
c-Myc, Sox2, and Klf4 [89,117]. These iPSCs pose identical self-re-
newal and multi-differentiation properties as ESCs and serve as a
prospective source of donor cells to eliminate or reduce the immune
rejection by using the iPSC-derived retinal cells from the patients.
Mouse and human iPSCs can differentiate into photoreceptors with
defined factors in vitro through the stepwise differentiation process
used in differentiation of ESCs [105]. In summary, the 2D-based pro-
tocols used in differentiation of ESCs or iPSCs toward photoreceptors
all proceed through an analogous regulatory pathway, including sup-
pression of endogenous BMP/TGFβ, Activin/Nodal and Wnt signal-
ing pathways with the addition of IGF-1 or Insulin and combination
with various regulatory factors (such as FGF1/FGF2/T3/ COCO),
retinoic acid (RA) and taurine [105,107,113,116-123].
To change the low differentiation efficacy observed in 2D culture
systems and establish robust protocols that provide a sufficient num-
ber of donor cells, mouse and human ESC-derived optic cups were
first generated in the Sasai lab using a 3D culture system; these optic
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cups are a significantly multilayered retinal tissue composed of major
neural retinal components, generally referred to as retinal organoids
[124,125]. Moreover, hiPSC-derived optic vesicle-like structures or
retinal organoids grown using 3D culture systems have also been es-
tablished [126-125]. On the basis of 3D retinal organoid technolo-
gy, many researchers have cultivated and produced a large number
of ESC/iPSC-derived photoreceptor cells for transplantation research
[129-146]. In this review, we will not go into too much detail.
In addition to generating transplantable cells or tissue, 3D reti-
nal organoid technology also holds great potential for in vitro disease
model, large-scale drug screening and testing, and cell development
exploration [147,148]. Patient iPSC-derived optic cups were used to
investigate the disease mechanism of hereditary blindness with the
common CEP290 mutation [146]. Most recently, our lab generated
iPSC-derived retinal organoids from RP patient with RPGR gene
mutations, which can monitor photoreceptor degeneration similar to
retinal morphology of the RP patient [149]. Interestingly, these de-
fects were partially rescued byCRISPR-Cas9-mediated correction of
RPGR mutation.
Derivation of Photoreceptor-Supportive RPE Cells
from Pluripotent Stem Cells
Considerable progress has been made in developing efficient pro-
tocols to direct differentiation of both ESCs and iPSCs into RPE cells,
and thus, a plentiful and controllable source of RPE cells can be ser-
viceable for cell transplantation therapy. An early study showed that
mouse ESCs were efficiently induced to differentiate into melano-
cytes in vitro [150]. Subsequent studies demonstrated that RPE cells
could also be derived from mouse and primate ESCs [151,152]. The
first hESC-derived RPE was generated using the original protocol, a
differentiation system without coculture using certain cells or factors
developed by Klimanskaya’s group [153]. Transcriptomics analysis
of hESC-derived RPE, mature RPE and human fetal RPE confirmed
that they are more similar to native RPE tissue than the existing hu-
man RPE cell lines. Vugler and colleagues found that hESC-derived
RPE cells express several markers associated with the development
and maturity of RPE cells, including Pax6, OTX1/2, RPE65 and
PMEL17 [154]. Although ESC-derived RPE cells have features very
similar to those of typical RPE cells in morphology and function, the
differences of in vitro cell maturity require further analysis to obtain
optimal transplant cell populations for transplantation. Theoretically,
an unlimited source of RPE cells can be harvested utilizing this cul-
ture system.
Since then, different labs have optimized the protocol to derive
pure and safe RPE cells from hESCs and iPSCs [116,155-167]. As
described earlier, iPSCs possess regenerative capability equivalent
to those of hESCs and thus are also used as another pluripotent cell
source for cell and tissue regeneration [89,115,167]. The process of
iPSC-derived RPE cell differentiation can be greatly promoted direct-
ed by inhibiting the signaling pathways of Wnt and Nodal in RPE
cells with the addition of factors such as Dkk1 and Lefty-A [172,173].
Morphologically and functionally, iPSC-derived RPE cells have the
similarity with native RPE and express RPE-specific markers.
In view of the fact iPSCs can be generated from any differenti-
ated somatic cells by induction with “Yamanaka factors” [89,174],
patient-specific iPSCs afford a potential cell replacement thera-
py that theoretically may circumvent immune rejection [175-177].
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DOI: 10.24966/SRDT-2060/100014
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In summary, iPSC-derived RPE cells are a promising cell source to
replace defective RPE cells in retinal degeneration.
Transplantation of Stem Cell-Derived Photorecep-
tors, RPE for Retinal Repair
Above, we have introduced stem cell sources of photoreceptors
from stem cells above that are considered efficient cell sources for
photoreceptor transplantation target to neuroretinal degenerative dis-
eases. From the first attempts at transplantation of human ESC-de-
rived neural progenitors into immunodeficient rats intravitreally and
subretinally, which showed an insufficient sources for photoreceptor
transplantation [178], to the preliminary successful research showing
that human ESC/iPSC-derived neural progenitors could effectively
protect vision in RCS rats (an AMD-like rat model) [179,180], the
cumulative findings during the past few decades have encouraged
researchers to further explore transplantation of retinal specific cell
types.
Transplantation of Stem Cell-Derived RPE Cells:
Preclinical Studies and Clinical Trials
Previous studies of allogeneic and xenogeneic replacement ther-
apy using autologous or mature RPE cells showed an unstable phe-
notype and a limited source of RPE cells, which provided a space
for development of cell replacement therapies using stem cell-derived
RPE [153,181-197]. Stem cell-derived RPE cells have been the focus
of replacement therapy for AMD and STGD, which are assigned to
macular disorders characterized by early loss of the RPE cells that
maintain the survival of photoreceptors.
ESC-derived RPE cells were first transplanted as a monolayer to
treat RPE dysfunction in RCS rats using primate ESCs and enhanced
the survival of the host photoreceptors [198]. Subsequently, hESC-de-
rived RPE cells were also utilized for subretinal transplantation in
RCS rats and Elovl4 mutant mice (a STGD-like mouse model) and
safely prompted preservation of visual function and production of
more photoreceptors [154,155,199-201]. Likewise, hiPSC-derived
RPE cells were also able to rescue vision in animal models of reti-
nal degeneration [185,202-205]. These preclinical studies have set an
encouraging and solid foundation for clinical trials of human ESC/
iPSC-derived RPE transplantation.
In 2011, the U.S. Food and Drug Administration approved phase
I/II clinical trials for ESC-derived RPE transplantation in the treat-
ment of macular degeneration [206]. According to the current reg-
istered clinical trials using stem cell-based therapies for STGD or
AMD (https://clinicaltrials.gov/), phase I and II clinical trials are in
progress for RPE replacement using hESC/iPSC-derived RPE cells
in single-cell suspensions or in monolayers seeded on scaffolds. The
preclinical study and clinical trial of hESC-derived RPE cell suspen-
sion (named MA09-RPE, forming a master cell bank of hESCs) for
treatment of non-neovascular AMD and advanced STGD was first
launched in America and primarily demonstrated the safety of sub-
retinal transplantation of hESC-derived RPE cell suspension [206-
208]. In addition, the potential efficacy has also been confirmed by
clinical trials (NCT02463344, NCT02563782) for non-neovascular
AMD using a cell suspension with immunosuppressive therapy as re-
sistance to rejection. Moreover, the same MA09-RPE cell suspension
was used to treat non-neovascular AMD and STGD in a phase I/IIa
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clinical trial in South Korea without abnormal proliferation and tumor
formation [209].
In addition to the above therapeutic strategies using a stem cell-de-
rived RPE cell suspension, an alternative optimized approach is to
grow RPE cells on a bioengineered scaffold to form an RPE mono-
layer before transplantation, which can improve resistance to adverse
events and produce polarized RPE cells in a highly functionalized cell
monolayer [210-214]. As with CPCB-RPE1, hESC-derived RPE cells
are seeded on a biosynthetic scaffold designed to mimic BM, pro-
duced as described previously [215,226]. Several preclinical studies
were performed to evaluate the transplantation effects of CPCB-RPE1
into the RCS rats and Yucatan mini pigs, and the results indicated
that CPCB-RPE1 implants survived in an intact monolayer without
development of intraocular or systemic tumors [215-217]. Then, the
safety and efficacy of CPCB-RPE1 transplantation was confirmed
in a phase I/II a clinical trial for non-neovascular AMD in America,
and visual improvement in the short term was observed in some pa-
tients. In England, an RPE patch named PF-05206388, composed of
hESC-derived RPE monolayer on a coated and synthetic basement
membrane, was implanted into the subretinal space of severe neovas-
cular AMD patients, resulting in an increase in visual acuity over 12
months. Unwilling to lag behind, China has initiated two phase 0/I
clinical trials for treatment of AMD conducted by Beijing Tongren
hospital (NCT02755428) and Southwest hospital (NCT02749734).
The phase I clinical trials for neovascular AMD (NCT02749734) us-
ing a hESC-derived RPE cell suspension showed a limited functional
improvement in vision, albeit to different degrees between patients
[205].
Implantation studies of hiPSC-derived RPE cells have lagged be-
hind those of hESC-derived RPE cells. However, allograft transplan-
tation of hESC-derived RPE requires lifelong immunosuppressive
therapy, and in contrast, iPSCs do not provoke an immune reaction
[218,219]. Due to allowance for autologous transplantation, reduction
of ethical issues and potentially unlimited cell sources, hiPSC-derived
RPE cells have become widely used. Moreover, particularly, patient
iPSC-derived RPE is considered the best in vitro disease modeling
candidate to visually and accessibly monitor progression of human
disease progression [197,220-222].
A preclinical study in Rpe65rd12/Rpe65rd12 mice showed that im-
plantation of hiPSC-derived RPE cell suspension into this mouse
model safely presented colocalization with the host native RPE cells
and restored modest vision detected by Electroretinogram (ERG)
[223]. Another preclinical study in RCS rats demonstrate that hiP-
SC-derived RPE cells have the ability to phagocytose photorecep-
tor material and maintain long-term visual function after transplan-
tation of a cell suspension [185]. The other preclinical studies in
RCS rats reported that transplantation of hiPSC-derived RPE cell
suspension exhibited protective effects and restored visual function.
[197,202,214,224].
To optimize the beneficial effects to host retinal function, an intact
donor hiPSC-derived RPE monolayer grown on biomaterial scaffolds
was implanted, similar to hESC-derived RPE. This novel approach
for hESC-derived RPE cells as apolarized monolayer on a thick syn-
thetic scaffold was first transplanted into RCS rats [225], and sub-
sequently, hESC-derived RPE cell patch or sheets on biodegradable
scaffolds were used for AMD treatment in rodents and pigs and pro-
vided positive results for clinical trials [226-228].
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DOI: 10.24966/SRDT-2060/100014
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The progress in iPSC replacement therapy is cruising to the clinic.
In 2013, a clinical trial authority for hiPSC-derived RPE into patient
treatment was approved in Japan [229]. In 2014, Takahashi’s group
from the RIKEN Institute safely performed the first transplantation
of autologous iPSC-derived RPE sheets for a female neovascular
AMD patient in clinical trial. However, in 2015, RIKEN suspended
the clinical trial for another patient due to genomic variations in iP-
SCs [230]. The landmark research results were finally published in
2017 and showed that the best visual acuity correction had not been
improved or worsened 1 year after transplantation [137]. Currently, a
novel clinical trial for autologous hiPSC-derived RPE transplantation
in AMD is ongoing by Moor fields eye hospital (NCT02464956).
Transplantation of Stem Cell-Derived Photoreceptors
The initial studies of photoreceptor replacement focused on photo-
receptors derived from donor tissues [231-233], which are known as
a very limited cell sources for clinical application. It was demonstrat-
ed that the development stage of donor cells influenced the grafting
outcomes, and post-mitotic photoreceptor precursors isolated from
P4 mouse retina were an optimal donor cell [231,234]. Then, trans-
plantation of these photoreceptor cells successfully restored func-
tional rod-mediated vision in Gnat1−/− mice [233], a model of con-
genital stationary night blindness with dysfunctional rods [235]. The
fact that less mature photoreceptor precursors derived from mouse
ESCs helped to improve transplantation success was again confirmed
[132,236].
Numerous transplantation studies [129,132,135,139,224,241-239]
have been subsequently performed with retinal cells differentiated
from mouse ESCs and iPSCs generated using the differentiation pro-
tocol reported by Eiraku and Tucker [124,224] (Table 1). To obtain
abundant photoreceptors derived from mouse ESC and iPSC and min-
imize potential tumor genesis from undifferentiated cells, cell-sorting
strategies have been used to purify miscellaneous cell populations
prior to transplantation [224,237]. These cell-sorting strategies via
Fluorescence Activated Cell Sorting (FACS) and Magnetic Acti-
vated Cell Sorting (MACS) were established based on the expres-
sion of photoreceptor-specific fluorescent reporters or cell surface
markers [233, 240-242]. They have been successfully used to purify
mouse ESC- and iPSC-derived photoreceptors before transplantation
[132,135,139,236,237]. These studies from different groups demon-
strated that mouse ESC- and iPSC-derived photoreceptors have the
competence to partially recover visual function in various mouse
models associated with RD.
In 1997, for the first time, a human photoreceptor obtained from
adult human cadaveric eyes was successfully implanted into two RP
patients but was unable to improve vision [243]. And transplantation
of human fetal retinal sheets into RP patients showed that they are ca-
pable of surviving and improving vision partially with no rejection of
the allogeneic transplant [244-246]. However, ethical issues and the
limited source of fetal tissue-derived retinal sheets are bound to make
it impossible to be used on a large scale.
Early, neural progenitors deriving from differentiation of hESCs
were implanted into immune-suppressed rats and non-immunosup-
pressed mouse retinas, and the results indicated that they could sur-
vive for a long time without tumor formation but differentiated into
photoreceptor-like cells with a low-level of efficiency [103,247].
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Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
Subsequently, following transplantation into RCS rats, neural progen-
itors deriving human ESC and iPSC continued to present uncommit-
ted progenitors with Nestin expression but no expression of specific
retinal markers [248,249]. However, vision loss was significantly
retarded in RCS rats although not completely halted, which may be
mediated by phagotrophic capacity toward photoreceptor outer seg-
ments or secretion of neurotrophic factors from the injected neural
progenitors [250].
In the earliest transplantation studies of human ESC- derived ret-
inal cells (80%), they were transplanted into the subretinal space of
Crx-/- mice (a mouse model of Leber’s Congenital Amaurosis) [251]
and differentiated into functional photoreceptors and restored light
responses in the mouse model 2–3 weeks after injection [107]. More-
over, human iPSC-derived photoreceptors purified via FACS in com-
bination with a photoreceptor-specific GFP marker could integrate
into the host ONL of adult wild-type mice, similar to normal mouse
photoreceptors and human ESC-derived rod photoreceptors [107].
Similarly, human ESC- and iPSC-derived photoreceptor progenitors,
following FACS or MACS sorting, differentiated into photoreceptors
after transplantation into rd1 mice, and integrated into the host retinal
neural circuit, restoring partial visual function [240]. In a recent study,
human iPSC-derived mature photoreceptors brought mild recovery of
host light perception when transplanted into rhodopsin mutant nude
rats and primate models of retinal degeneration [252].
For the rod-dominated mouse retina, transplantation of donor rod
photoreceptors into murine models of retinal disease improved vision
to different degrees [233,234,240,253]. Theoretically, for cone-dom-
inated human retinas, cone photoreceptor replacement should be the
optimal strategy for treatment of human retinal degeneration. Sever-
al reports of cone transplantation showed a detectable restoration of
visual function using a variety of cone and cone-like donor cells in
degenerative hosts [238,254-256], which resulted from donor cone
integration into degenerative retina. Meanwhile, a significant propor-
tion of material transfer between donor cells and the host retina was
observed in non-degenerative hosts [238, 254-261].
These clinical trials mentioned above for treating RD using stem
cell-derived RPE have aroused a strong interest in promoting stem
cell-derived photoreceptors toward clinical applications. One land-
mark step is that human ESC lines for therapeutic purposes have been
derived from Good Manufacturing Practices (GMP)-compliant xe-
no-free and feeder-free protocols [262]. Moreover, fullly GMP-com-
pliant human iPSC lines have been generated from adult fibroblasts
with different inherited retinal diseases in patients [263]. Then, hu-
man ESC- and iPSC-derived photoreceptors were generated using
feeder-free and xeno-free GMP conditions [125,127, 263-265].
Strategies for Delivering Stem Cell-Derived Photo-
receptors, RPE Cells
Stem cell-derived retinal cells are often injected into the eye via
direct injection intravitreally or subretinally. Intravitreal injection is
easier and less invasive and provides a more access to the Inner Reti-
nal Layer (INL). However, this delivery route is associated with a risk
of short-term complications, including retinal detachment, endoph-
thalmitis, and hemorrhage [266,267].
Subretinal injection offers a direct and effective route to deliver
donor cells with more precise localization via a minimally invasive
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DOI: 10.24966/SRDT-2060/100014
• Page 6 of 22 •
injection [206,268]. To avoid the complications and improve the in-
jection effectiveness, subretinal delivery requires skill and stability
until mastered. The routes of subretinal injection can be classified into
three types: a trans-corneal route passing the lens and vitreous humor
[269-272], a trans-scleral route entering the pars plana at the limbus
or ora serrata [273-276]; and a transscleral route through the choroid
and BM without penetrating the retina [277-279]. The choice of dif-
ferent routes depends on the anatomy of the eyeball according to the
species and age. Bleb formation in the subretinal space, come down
to retinal detachment that creates a space between the outer segment
of the photoreceptor and the RPE, is defined as a successful sign of
injection.
Delivering Stem Cell-Derived RPE
Stem cell-derived RPE is implanted into the subretinal space as
an isolated cell suspension or monolayer on a scaffold [285,286].
After subretinal injection, the scattered RPE cell suspension forms
aggregates without an intact monolayer, initiates an immune response
[282], and causes severe complications, such as proliferative vitreo-
retinopathy [215,283]. The use of biocompatible scaffolds [283-287]
could avoid these issues and enables proper subretinal delivery of
stem cell-derived RPE cells as a monolayer structure for transplan-
tation [288]. Thus, monolayer RPE sheets can be constructed with
naturally occurring polymers or synthetic scaffolds. Natural materi-
als are reported to potentially cause a series of issues, such as risk
of infection, difficulties controlling the consistency of the material,
and mechanical instability [289,290]. Synthetic scaffolds are widely
used due to their biocompatibility, ability to imitate the native Extra-
cellular Matrix (ECM), and biodegradability [291-293]. Particularly,
parylene, an undegradable synthetic material, is widely used in RPE
sheet construction to aid in an intact formation of polarized monolay-
er without disruption of host RPE structure [210,216,294], which can
promote donor RPE cells to survive and integrate into the host RPE
[216]. As mentioned above, CPCB-RPE1, an hESC-derived RPE
monolayer seeded on an ultrathin polymeric parylene-C scaffold, has
been tested in a clinical trial [215,216]. Studies of other synthetic ma-
terials (i.e., PLGA, PET, and PCL) are also ongoing [225,295-297]. In
addition, RPE sheet can be generated on a collagen coating without an
additional scaffold and then released from the digested collagen coat-
ing [226]. Furthermore, a human iPSC-derived RPE sheet generated
using this strategy has been transplanted onto one AMD patient [137].
Scaffold-based subretinal delivery requires a larger retinotomy
into the subretinal space compared with dispersed cell delivery, and
some efforts have to be made for more subtle manipulation and small-
er microfabrication.
Delivering Stem Cell-Derived Photoreceptors
The challenges of photoreceptor transplantation primarily involve
how to improve the survival rate of transplanted photoreceptors and
promote integration of transplanted cells with the host retina to re-
store vision function. The key step in photoreceptor transplantation is
to guarantee effective delivery of donor photoreceptors into the host
subretinal space. The strategies for donor photoreceptor delivery can
primarily be divided into three approaches: injection of photorecep-
tor cell suspensions, transplantation of intact retinal or photoreceptor
sheets and transplantation of photoreceptors seeded onto engineered
scaffolds. Although these approaches have been applied for treatment
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Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
of photoreceptor degeneration and achieved an encouraging result,
there is no single approach that perfectly solves all the problems
[236,283,298-303].
Before transplantation studies toward stem cell-derived photorecep-
tors, transplantation of primary photoreceptors achieved considerable
progress using a single-cell suspension approach [233,253,255,304].
Then, cell suspension transplantation of ESC- and iPSC-derived pho-
toreceptors into mouse models of RD improved vision function as
measured by ERG [107,109,224,305]. Notwithstanding the tactic of
cell suspension transplantation has some crucial advantages, includ-
ing precise control of the number of transplanted cells and minimally
invasive delivery via subretinal injection [107,109,224,305], it also
has some unexpected disadvantages, including high incidence of cell
death of transplanted cells and low rates of cell survival and integra-
tion [129,306-309].
Transplantation of retinal sheets has been studied as an alternative
tactics for photoreceptor replacement in RD. Many previous studies
of photoreceptor replacement focused on the usage of intact retinal
or photoreceptor sheets [232,243,246,310-312], but these individuals
with these transplants presented large variations in visual function re-
covery. Similarly, mouse ESC- and iPSC-derived retinal sheets differ-
entiated into mature photoreceptors with OSs and integrated into the
host retina, restoring partial vision after transplantation into rd1 mice
[129,239]; but hESC-derived retinal sheets were successfully trans-
planted into monkey and rat models of retinal degeneration, and then
matured into structured grafts without positive functional changes in
monkeys and resulted in visual function recovery as measured by Op-
tokinetic Testing (OKT) in rats [313,314]. In addition to variations in
visual function recovery, retinal sheet transplantation relatively high-
ly invasive for the patient and often leads to an immune response to
the transplants [315,316] compared with single-cell suspension.
To further improve photoreceptor transplantation, biomaterial
scaffolds designed for photoreceptor delivery have been developed.
They can enhance cell survival and promote cell integration into the
host retina. Many biomaterial scaffolds have been constructed using
multiple polymers alone or jointly, such as PHBV8, PLLA, PLGA,
PMMA, PGS, PCL, HA, PDMS, and MC, and have been applied in
transplantation of mouse or porcine RPCs [288,306-308,317-322].
Biodegradable scaffolds with high permeability have an insurmount-
able advantage in promoting photoreceptor survival with nutrient and
oxygen diffusion [225,304,318].
Furthermore, recent studies showed that 3D micro structured scaf-
folds promote efficient polarization of human iPSC-derived photo-
receptors and basal axon extensions [323]. And two-photon polym-
erized polycaprolactone successfully supported human iPSC-derived
retinal progenitor cells for implantation into a porcine model of
retinitis pigmentosa [297]. These pioneering studies on the delivery
of stem cell-derived photoreceptors combined with biomaterial scaf-
folds pave the way for future photoreceptor transplantation therapies.
Taken together, these strategies for delivering stem cell-derived
retinal cells in combination with biodegradable scaffolds are very
promising advanced techniques to treat and even cure neuroretinal
diseases in the future.
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DOI: 10.24966/SRDT-2060/100014
• Page 7 of 22 •
Future Directions and Challenges Ahead for Photo-
receptor Regeneration
As described above, stem cell-based therapies for neuroretinal dis-
eases have achieved unprecedented progress in the last decades. With
the progress in cell transplantation therapies, perhaps in the next 10
years, some neuroretinal diseases will be completely cured. Currently,
transplantation studies of different stem cell-derived retinal cells are
at different stages of development. Stem cell-derived RPE transplan-
tation has been pushed into clinical trials and produced positive pre-
clinical data. Due to the complex circuitry of photoreceptors within
the inner retina or optic nerve, stem cell-derived photoreceptor re-
placement still lies at the preclinical study level with positive results.
In short, different grand challenges exist for the two cell transplanta-
tion therapies and remain to be overcome in the future.
Stem Cell-Derived RPE Transplantation
ESC- and iPSC-derived RPE transplantation has been per-
formed in numerous preclinical studies [154,155,185,197-199,215-
217,225,226,228,324,325] and clinical trials [137,206-208,326,327].
After human ESC-derived RPE transplantation into AMD or STGD
patients, no tumor formation or immunological rejection was ob-
served, confirming the safety [326,328]. However, no significant
visual improvement was observed despite visible pigmentation and
thickening of the RPE layer in the host retina detected by noninvasive
fundus photography and Spectral Domain Optical Coherence Tomog-
raphy (SD-OCT). Therefore, it is especially urgent to explore new
strategies to promote curative effects.
The viability of RPE cells was significantly promoted by culture
in Hyaluronan-Methylcellulose (HAMC) hydrogel combined with
IGF-1 factor, which was illuminated by a study in which dual-use
biocompatible materials can be used as drug delivery platforms or to
encapsulate cells [329,330], indicating that strategies for co-delivery
of growth factors and retinal cells to improve the curative effects of
stem cell-derived RPE transplantation are promising. Future research
needs to focus on this interesting point.
Additionally, human iPSC-derived RPE has been reported [331]
to exhibit differential expression of ES-associated miRNAs compared
with human fetal RPE, and thus underscoring the importance of as-
sessing human iPSC-derived RPE completely before transplantation.
Moreover, a clinical trial was suspended due to genomic variations
found in the transplanted human allogeneic iPSCs [230], which may
have a potential risk of tumorigenicity. To improve the reliability of
stem cell-based treatment, donor iPSCs or iPSC-derived RPE cells
must be subjected to extensive testing. Donor iPSCs induced from au-
tologous somatic cells will be a good choice for stem cell-based treat-
ment. For future allogeneic trials, a GMP-compliant bank of iPSCs,
similar to that of ESCs, should be gradually established in all qual-
ified medical institutions [230]. And these cells should be matched
with patient Human Leukocyte Antigens (HLAs), thereby reducing
the risk of immunological rejection [332-335].
In addition to the above burning problems, standardized cell dif-
ferentiation, high-efficiency cell delivery, preferable safety evalua-
tion, most suitable phase for transplantation therapies and therapeutic
analysis are all unremitting pursuits for future clinical trials.
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Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
Stem Cell-Derived Photoreceptor Transplantation
A number of transplantation studies using stem cell-derived pho-
toreceptors have been carried out in many photoreceptor-deficient
animal models (Table 1). Although the integration of transplanted
photoreceptors into host retinas has been reported in some previous
studies [107,237,240,336], vision improvement was not significantly
observed due to insufficient integration of cells. Therefore, the first
issue is how to obtained sufficient donor cells in an efficient and reli-
able manner. To overcome this issue, on the basis of fully GMP-com-
pliant generation of human ESC- and iPSC-derived photoreceptors
[125,127,263,265,337], an efficient and reliable cell sorting strategy
could be added to the GMP guidelines. Certain cell-specific surface
antigens (CD73 or C-Kit) have been used as markers for sorting pho-
toreceptors from human fetal retinas or stem cell-derived organoids
via MACS or FACS [205,338-340]. In the future, achievement of a
GMP-compliant photoreceptor sorting strategy will lay the founda-
tion for acquiring appropriate donor cells.
The second outstanding issue is how to interpret and identify ma-
terial transfer or cell integration between donor cells and host retina
after photoreceptor transplantation into animal models. Before mate-
rial transfer (RNA and/or protein) was found in donor cells and host
photoreceptors [257,258,341], the therapeutic efficiency of photore-
ceptor replacement was attributed to its integration into the host retina
and differentiation of rods [107,109,233,234]. Human ESC- and iP-
SC-derived photoreceptors have been confirmed to integrate and form
synaptic connections with host cells that result in vision improvement
[129,239,305], and material transfer and cell integration could occur
at the same time at different ratios [339,342-345]. However, more
work needs to be performed to illuminate the cellular mechanisms of
this phenomenon.
The third general issue is how to improve the effectiveness of
treatments based on human iPSC-derived photoreceptor transplan-
tation. As is known, autologous transplantation of photoreceptors
derived from the patient’s own iPSCs will evade immunological re-
jection. However, iPSCs from patients still carry the disease-causing
gene mutations, leading to potential risk of pathopoiesis after trans-
plantation. CRISPR-Cas9 gene editing technology allows modifica-
tion of the gene mutations in patient iPSCs during in vitro culture
[346]. Our group has corrected an RPGR mutation in patient iPSCs
using CRISPR/Cas9 gene editing technology in vitro, which rescued
photoreceptor structure and electrophysiological property in retinal
organoids derived from these iPSCs [149]. Therefore, human iP-
SC-derived photoreceptors with CRISPR-Cas9-mediated correction
will be a promising strategy for treatment of inherited retinal disor-
ders.
How to definitively solve cone transplantation is also a worthy con-
cern. Previously, the vast majority of studies primarily focused on rod
transplantation and demonstrated that transplanted donor rod photore-
ceptors possess the ability to rescue vision impairment in rodent mod-
els of retinal diseases [109,190,231,234,236,240,256,303,339,342-
345,347]. Notwithstanding, cone transplantation has also been
reported recently [254-256], and these transplanted donor cones were
characterized by rod-like morphological features, which were deemed
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DOI: 10.24966/SRDT-2060/100014
• Page 8 of 22 •
to result from cell integration and/or material transfer determined by
the different host microenvironments [238], but detailed mechanisms
need to be further explored to improve the efficiency of cone trans-
plantation.
Actually, the influencing factors in photoreceptor transplantation
are more than those mentioned above. Suitable preclinical animal
models, immune rejection, tumor formation, cell survival, and deliv-
ery systems should all be further optimized carefully and continuous-
ly before clinical trials.
The Expected Role of Retinal Glial Cells in Stem
Cell-Based Therapy for Neuroretinal Diseases
Not only that, a new strategy for stem cell-based combined trans-
plantation has been developed to treat various no-ocular diseases or
injury such as severe aplastic anemia [348], acute blood loss [349],
Graft Versus Host Disease (GVHD) [350], myocardial infarction
[351], diabetes [352], and cavernous nerve injury-related erectile
dysfunction [33]. And these studies of combined transplantation
confirmed a more positive and encouraging result than that of single
transplantation. Previous studies have demonstrated that MSCs were
able to promote the survival and functionalization of retinal cells af-
ter single transplantation through secretion of neuroprotective factors
and deactivation of inflammatory pathway [354-356]. As expected,
combined transplantation of human RPCs and MSCs into subretinal
space of RCS rats presented better therapeutic effect in functional
maintenance and structural integration than that of single transplanta-
tion [357]. Likewise, in vivo intravitreal combined transplantation of
human iPSCs and mouse RGCs facilitated RGC neurites into longer
extension than single transplantation of mouse RGCs [358]. There-
fore, for treating neuroretinal diseases effectively, a new co transplan-
tation tactics in combination with stem cell-derived photoreceptors
or RPE cells appears to be a promising way to give full play to the
effects of transplanted cells. Microglia is selected as targeted cells
for combined transplantation with stem cell-derived photoreceptors
or RPE cells.
Microglia are a group of highly specialized immune cells and
widely exist in CNS, including retina, which play a pivotal role in
immune surveillance and maintaining homeostasis of retinal micro-
environment [359,360]. Microglia has been confirmed to have neu-
roprotective effects against neuronal death in ischemic brain injury
[361,362]. And microglia is also capable of phagocytizing injured
photoreceptors and preventing the death of photoreceptors in acute
retinal detachment [363]. Recent studies further demonstrated that
subretinal microglia in photoreceptor degeneration played an import-
ant role in protection of RPE structural integrity [364]. Therefore, mi-
croglia should be able to improve subretinal microenvironment prior
to transplantation suitable for the survival of transplanted photore-
ceptors or RPE cells. In addition, microglia can be generated from
induction of human ESCs and iPSC [365,366], providing sufficient
cell sources for combined transplantation studies. Taken together,
combined transplantation of stem cell-derived microglia and photo-
receptors or RPE cells will become the next another target to treat
neuroretinal diseases.
Moreover, as mentioned above, Müller Glia (MG) are also promis-
ing targeted cells to be directly reactivated and differentiate into new
retinal neurons in vivo with the development of induced techniques.
Volume 5 • Issue 1 • 100014
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• Page 9 of 22 •

Donor cell Host animal Time window Delivery Time point for Effects of trans-
Target diseases Cell dose Reference
sources models (postnatal) methods evaluation plantation

Transplanted cells
migrated and
Total 2 μl con-
integrated into the
taining 1 μl cell
Human MG-de- ONL
Transgenic P23H Retinitis Pigmen- suspension and 4 Subretinal 4 weeks after
rived photore- 3 weeks Significant rod [80]
rats [367] tosa (RP) × 104 photorecep- injection transplantation
ceptors function improve-
tor differentiated
ment measured
cells
by scotopic flash
ERG

Combined
transplantation
Total 4 × 105 has a higher ratio
Human RPCs cells/5 μl 3 weeks after of photoreceptor
[357]
and MSCs RCS rats with separately and transplantation differentiation and
together Subretinal low immunore-
Mertk mutation RP 3 weeks
injection action than single
[368]
transplantation

Preserve visual
5× 104-1× 105 3-6 months after
Human RPCs function measured [376]
cells/2 μL transplantation
by OKR

Rho−/− mice [373] RP 6-12weeks

No robust integra-
Mouse ESC-de-
Subretinal injec- tion and maturation
rived rod photo- Leber congenital 2× 10 cells/1 μl
5
2-3 weeks after
Gucy2e-/-mice [371] tion via superior of photoreceptors [96]
receptors using amaurosis (LCA) sorted by FACS transplantation
sclera Increased cell
2D culture 8-12weeks
death and gliosis
Congenital
Gnat-/- mice [235] stationary night
blindness(CSNB)

2.5 × 104 integrated

cells
form long outer
segments
Gnat1−/− mice [235] CSNB 8-12 weeks
Mouse ESC-de- Vision restoration
Subretinal
rived rod photo- 2× 10 cells/1 μl
5
measured by water
injection by 3 weeks after [372]
receptors using sorted by FACS maze and optome-
trans-scleral route transplantation
3D culture try system

Rho−/− mice [379] 3-4 weeks

Form shorter
Prph2 mice
rd2/rd2 RP
8 weeks segments
[374]

Mouse 1.1.6 × 105 inte-

iPSC-derived grated cells
Subretinal 3 weeks after
photoreceptor Rho−/− mice [373] RP 2.5× 105 cells/lμl 4-6 week 2. Increased [224]
injection transplantation
precursors using b-wave amplitude
2D culture measured by ERG

Photorecep-
tor responses
Mouse iPSC-de-
recorded by ex
rived retinal Pde6brd1 mouse 0.5 mm × 2 mm Subretinal 2-4 weeks after
RP 6-9 weeks vivo micro-ERG [239]
sheets using 3D [375] retinal sheets injection transplantation
and ganglion cell
culture
responses recorded
MEA

Mouse ESC/
iPSC 2 weeks to 6
Pde6brd1 mouse 0.5 mm x 1.5-2 Subretinal Form synaptic
derived retinal RP 6-8 weeks months after [129]
[375] mm retinal sheets injection connections
sheet using 3D transplantation
culture

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal Volume 5 • Issue 1 • 100014
DOI: 10.24966/SRDT-2060/100014
Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.

• Page 10 of 22 •

“Cod” hybrid Significant materi-

Nrl−/− mice [376]
phenotype al transfer
Mouse ESC-de-
Subretinal
rived cone 2× 105 cells/1 μL 2-3 weeks after Significant cones
Prph2rd2/rd2 [374] RP 2-3 months injection by [238]
photoreceptors sorted by FACS transplantation integration
trans-scleral route
using 3D culture
RPE65R91W/R91W Cone degener- Significant materi-
[377] ation al transfer

1.3 × 103Nrl+
Human
0-3 days integrated human
ESC-derived Intravitreal
5× 104-8× 104 (intravitreal) 2 weeks after cells
photoreceptor Crx -/- mice [379] LCA and subretinal [107]
cells/1 μL and 4-6 weeks transplantation 2. A small,
precursors using injections
(subretinal) significant ERG
2D culture
response

Survival and
maturation in vivo
of few transplanted
Human
cells
ESC- and Subretinal
Pde6brd1 mouse 3 weeks after Partial vision
iPSC-derived RP 2 × 105 cells/2μL 10-12 weeks injection by [109]
[375] transplantation recovery measured
photoreceptor trans-scleral route
by optomotor
progenitors
response (OMR)
and light avoidance
behavior

RP-like monkey Lack positive

model induced by 35, 88, 123, and functional results
cobalt chloride or 4,5,6,9,11 years 148 days after  Differentiation [313]
laser photocoagula- transplantation into various retinal
tion [313] cells

Produce functional
Human ESC-de- photoreceptor
rived retinal Immunodeficient Subretinal Visual improve-
RP Retinal sheets 2 weeks after
sheets using 3D rho S334ter-3 rat 26-38 days injection ments measured [381]
transplantation
culture [380] by OKR and SC
electrophysiologic
recording

Long-term survival
Immunodeficient Functional inte-
4 weeks after
NOG-rd1-2J and 8 weeks gration [382]
transplantation
NOG-rd10 [382] Light responses
measured by MEA

Formation of outer
segments and in-
Immunodefi-
tegration into host
cient SD-Foxn1 3-5 months after
2-5 months bipolar cells
Tg(S334ter)3LavR- transplantation
Human iPSC-de- Observed RGC
rrc nude rats [383] Subretinal injec-
rived retinal light responses by
RP Retinal sheets tion by trans-vit- MEA [252]
sheets using 3D
real route
culture RP-like monkey
Mild vision recov-
model induced by
6-7 months after ery measured by
cobalt chloride or 9 months
transplantation Visually-Guided
laser photocoagula-
Saccades (VGS)
tion [313]

Table 1: Representative stem cell transplantation studies in animal models of photoreceptor-defective diseases.

Conclusion Competing Interest

In terms of depth and breadth, translational medicine studies on
stem cell transplantation for treatment of neuroretinal diseases have
made considerable progress. Although these encouraging advances
have brought great hope to the treatment of neuroretinal diseases,
there are still big challenges ahead that need to be further explored
and overcome. The new techniques of stem cell-based transplantation
are also worthy of unwearied pursuit.
The author declares that has no competing interests.
Acknowledgment
This work was partly supported by Zhejiang Provincial Natural
Science Foundation of China (LQ17H120005); National Key Re-
search and Development Program of China (2017YFA0105300);
Ministry of Education 111 project (D16011).

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal Volume 5 • Issue 1 • 100014
DOI: 10.24966/SRDT-2060/100014
Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.
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