Neural stem cells transplanted to the subretinal space of rd1 mice delay retinal degeneration by suppressing microglia activation.

Abstract:

BACKGROUND AIMS:Retinal degeneration (RD) is an inherited eye disease characterized by irreversible photoreceptor loss. Conventionally, the activation of the resident microglia is secondary to the disease. Stem cell-based therapy has recently made rapid progress in treating RD. Although it has been demonstrated that the effect of stem cell therapy may include immunomodulation, the specific mechanisms have not been clarified. METHODS:Immunocytochemistry, terminal deoxynucleotidyl transferase UTP nick end labelling (TUNEL) assay and Western blot were used to analyze the microglia activation and photoreceptor apoptosis in the retina of rd1 mice. GFP-C17.2 neural stem cells (NSCs) were transplanted into the subretinal space to study the immunomodulatory and neuroprotective effects. The transwell co-culture of BV2 cells with GFP-C17.2 was performed to study the proliferation, apoptosis and secretion levels of inflammatory factors. Real time-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were performed to explore the gene and protein level of factors secreted by NSCs and microglia. RESULTS:TUNEL-positive cells were primarily distributed in the inner nuclear layer (INL) of rd1 mice on P8d, appeared in the outer nuclear layer (ONL) on P10d and peaked on P14d. Meanwhile, microglia migrated to the ONL and reached the maximum level, accompanied by the changes in the levels of fractalkine and its unique receptor CX3CR1 protein. After transplantation of NSCs on P7d into the subretinal space of rd1 mice, the activated microglia were inhibited and the degeneration of ONL was delayed. In addition, microglia activation was suppressed by co-cultured NSCs in vitro. The gene and protein level of tissue inhibitor of metalloproteinase (TIMP1) in NSCs was elevated, whereas that of matrix metalloproteinase (MMP9) in BV2 microglia was markedly suppressed in this co-culture system. CONCLUSIONS:Transplanted NSCs in the retina exerted immunomodulatory effects on microglia, thus delaying the degeneration of photoreceptors.

journal_name

Cytotherapy

journal_title

Cytotherapy

authors

Li Z,Zeng Y,Chen X,Li Q,Wu W,Xue L,Xu H,Yin ZQ

doi

10.1016/j.jcyt.2016.03.001

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

771-84

issue

6

eissn

1465-3249

issn

1477-2566

pii

S1465-3249(16)30009-3

journal_volume

18

pub_type

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