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Page 194 Ma et al. J Transl Genet Genom 2022;6:179-203 https://dx.doi.org/10.20517/jtgg.2021.48

harvested from fetal tissues and extraembryonic tissues including placenta, amnion, amniotic fluid, and
umbilical cord [205-207] . Numerous sources of MSCs have been found, but MSCs derived from bone marrow
and adipose tissue are the main sources in current cell therapies. Due to its immunoregulatory capacity and
[208]
immune privileges, MSCs have been applied in multi-system disease .

MSCs work both on innate immune response and adaptive immune response: MSCs induce division arrest
[210]
[209]
anergy of immune cells ; prevent maturation of dendritic cells and activation of natural killer cells ;
inhibit proliferation, differentiation, and chemotaxis of B cells; interfere with antibody production of B
[211]
[212]
cells ; and induce T cell unresponsiveness by altering antigen-presenting cell maturation . MSCs can
migrate to sites of disease or injury and work as trophic mediators to release a broad range of bioactive
molecules including growth factors, cytokines, and chemokines .
[213]
MSCs exert their therapeutic potential by paracrine effects instead of differentiating into tissue-specific
cells . A wide array of proangiogenic cytokines, such as VEGF, basic fibroblast growth factor (bFGF), and
[214]
placental growth factor (PlGF), can be detected in the conditioned media of MSCs. Injection of the MSC
media into murine ischemic limb markedly enhanced the limb’s perfusion . Due to decreased choroidal
[215]
perfusion and hypoxia of sclera in highly myopic patients, the conditioned media of MSCs offers a good
option to modify the hypoxic circumstance of sclera. By injection of MSC conditioned media into the sub-
Tenon’s space or suprachoroidal space, it can exert its angiogenic effect without the risk of tumorigenesis.

In addition to subretinal transplantation of iPSC-RPE, myofibroblasts, sclera stem cells, and MSCs are
methods for posterior scleral reinforcement [Figure 4].

What challenges will we meet?
Although we can see the bright prospect of stem cell-based therapy for myopic maculopathy, there are
several problems we need to consider.

When is the best therapeutic window?
In myopic patients with patchy or macular atrophy, subretinal transplantation of iPSC-RPE is a good choice
to reduce the loss of photoreceptors secondary to RPE loss. However, the best therapeutic window is hard to
elucidate. In patients with severe loss of photoreceptors, transplantation of sole RPE is of no help. Another
situation is when patchy atrophy develops, sparing the fovea, and the patient maintains good visual acuity.
In this case, a surgery with subretinal transplantation of iPSC-RPE poses a great risk to vision.

Difficulties in surgical technique
During the PPV surgery of subretinal transplantation of iPSC-RPE, experienced surgeons are required.
Subretinal injections of RPE cell suspension or subretinal placement of RPE cell patch, especially in high
myopia patients with thin retina, are elaborate procedures. The surgeons need to prevent transplanted cells
from dispersing into the vitreous cavity, or they need to keep the cell patch in a specific position. In
addition, specific surgical instruments are required. For example, a 25/41 G dual-bore cannula is used for
subretinal bleb creation , and a special instrument is required for subretinal cell patch delivery.
[216]

CONCLUSION
Until now, the pathogenesis of pathologic myopia is still unclear. The only way to improve the prognosis of
patients with pathologic myopia is to prevent the development of myopic maculopathy and restrain it in
time. Anti-VEGF agents have partially preserved the vision of patients with mCNV, but the majority of
patients with a higher level of myopic maculopathy face a high risk of visual loss. Eliminating blindness is