retinal progenitor cells
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2021 ◽  
Vol 12 ◽  
Author(s):  
Min Chen ◽  
Chunge Ren ◽  
Bangqi Ren ◽  
Yajie Fang ◽  
Qiyou Li ◽  
...  

Retinal degeneration is a leading cause of irreversible vision impairment and blindness worldwide. Previous studies indicate that subretinal injection of human retinal progenitor cells (hRPCs) can delay the progression of retinal degeneration, preserve retinal function, and protect photoreceptor cells from death, albeit the mechanism is not well understood. In this study, small extracellular vesicles derived from hRPCs (hRPC-sEVs) were injected into the subretinal space of retinal dystrophic RCS rats. We find that hRPC-sEVs significantly preserve the function of retina and thickness of the outer nuclear layer (ONL), reduce the apoptosis of photoreceptors in the ONL, and suppress the inflammatory response in the retina of RCS rats. In vitro, we have shown that hRPC-sEV treatment could significantly reserve the low-glucose preconditioned apoptosis of photoreceptors and reduce the expression of pro-inflammatory cytokines in microglia. Pathway analysis predicted the target genes of hRPC-sEV microRNAs involved in inflammation related biological processes and significantly enriched in processes autophagy, signal release, regulation of neuron death, and cell cycle. Collectively, our study suggests that hRPC-sEVs might be a favorable agent to delay retinal degeneration and highlights as a new paradigm for cell-free therapy.


2021 ◽  
Author(s):  
Jian Ma ◽  
Xiaoyun Fang ◽  
Min Chen ◽  
Yao Wang ◽  
Li Zhang

Abstract Background: Therapeutic applications of retinal progenitor cells (RPCs) are hindered by their limited proliferation and differentiation capacity and poor ability to migrate into damaged retinal tissue. Our study aimed to explore the effects of HA-CD44 interactions on the regulation of RPCs migration, proliferation and differentiation, and to investigate the underlying regulation mechanisms.Methods: Mouse RPCs were isolated and amplified. Western blot and flow cytometry analyses were used to investigate the expression of CD44 in RPCs. The effects of HA-CD44 interactions on the RPCs behaviors, including migration, proliferation and differentiation, were investigated by MTT assay, CCK8 assay, vertical collagen gel invasion assay, time-lapse imaging, immunocytochemistry, RT-PCR and western blot assay. Furthermore, the downstream signals of HA-CD44 interactions were investigated.Results: CD44 was expressed in RPCs, and HA-CD44 interaction markedly improved RPCs adhesion and migration. The stimulation of miR-21 expression by HA-CD44 interaction was PKC/Nanog-dependent in RPCs. Treatment of RPCs with PKC- or Nanog-specific ASODN or miR-21 antagomir effectively blocked HA-mediated RPCs adhesion and migration. Moreover, ROK/Gab-1 associated PI3K/AKT signaling activation was required in the HA-CD44 interaction mediated RPCs proliferation and neuronal differentiation.Conclusions: Our findings demonstrated new roles for HA-CD44 interaction in regulating both migration, proliferation and neuronal differentiation of RPCs. HA-CD44 signaling could comprise a novel approach to control RPC fates, which may be instructive for the application of RPCs for future therapeutic application.


2021 ◽  
Author(s):  
Christina Brown ◽  
Patrina Agosta ◽  
Christina McKee ◽  
Keegan Walker ◽  
Matteo Mazzella ◽  
...  

Retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP) have no treatment. Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. We investigated a novel approach in which human retinal progenitor cells (RPCs) derived from primitive mesenchymal stem cells (pMSCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Intravitreally transplanted cells improved retinal function and significantly increased retinal thickness. Transplanted cells homed, survived, and integrated to various retinal layers. They also induced anti-inflammatory and neuroprotective responses and upregulated neurogenesis genes. We found that RPCs were more efficacious than pMSCs in improving the retinal structure and function. RNA analyses suggest that RPCs promote neuroprotection and neuronal differentiation by activating JAK/STAT and MAPK, and inhibiting BMP signaling pathways. These promising results provide the basis for clinical studies to treat RDD using RPCs derived from pMSCs.


2021 ◽  
Author(s):  
Xi Chen ◽  
Shanshan Li ◽  
Xiaoli Liu ◽  
Jingjie Zhao ◽  
Xiufen Yang ◽  
...  

Abstract Background c-Kit/CD117, expressed in a series of tissue-specific progenitor cells, plays an important role in tissue regeneration and tissue homeostasis. We previously demonstrated that organoid-derived c-Kit+ retinal progenitor cells can facilitate the restoration of degenerated retina. Meanwhile, we have identified a population of endogenous c-Kit+ cells in retinas of adult mouse. However, the exact role of these cells in retinal degeneration remains unclear. Methods Retinal degeneration was induced by intravitreal injection of N-methyl-D-aspartate (NMDA). Two days post NMDA challenge, intravitreal injection of stem cell factor (SCF) was performed. Distribution and abundance of c-Kit+ cells and other retinal cells were evaluated by immunochemistry. Retinal function of treated mice was tested via flash electroretinogram (fERG) and the light/dark transition test. Possible regulatory pathways were evaluated by RNA sequencing. Results NMDA challenge increased the total number of c-Kit+ cells in the retinal ganglion cell layer (GCL), while slightly deregulated the protein level of SCF, which is mainly expressed in Müller cells. Both fERG and light/dark transition tests showed that intravitreal injection of SCF effectively improve the visual function of NMDA-treated mice. Consistently, the activation of microglia in injured retina has also been inhibited after SCF treatment. Mechanistically, SCF administration not only prevent the loss of retinal ganglion cells (RGCs), but also maintained the function of RGCs as quantified by fERG. Further, we performed transcriptome sequencing analysis of the retinal cells isolated from SCF-treated mice and the parallel control. Gene Ontology analysis showed that SCF-induced transcriptome changes were closely correlated with eye development-related pathways. Crystallins and several protective factors such as Pitx3 were significantly upregulated by SCF treatment. Conclusions Our results revealed the role of c-Kit+ cells in the protection of RGCs in NMDA-treated mice, via inhibiting the loss of RGCs. Administration of SCF can act as a potent strategy for treating retinal degeneration-related diseases.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Atefeh Atefi ◽  
Pendar Shojaei Kojouri ◽  
Fereshteh Karamali ◽  
Shiva Irani ◽  
Mohammad Hossein Nasr-Esfahani

Abstract Background In retinal degenerative disease, progressive and debilitating conditions result in deterioration of retinal cells and visual loss. In human, retina lacks the inherent capacity for regeneration. Therefore, regeneration of retinal layer from human retinal progenitor cells (hRPCs) is a challenging task and restricted in vitro maintenance of hRPCs remains as the main hurdle. Retina and anterior neural fold homeobox gene (RAX) play critical roles in developing retina and maintenance of hRPCs. In this study, for the first time regulatory regions of human RAX gene with potential promoter activity were experimentally investigated. Results For this purpose, after in silico analysis of regulatory regions of human RAX gene, the expression of EGFP reporter derived by putative promoter sequences was first evaluated in 293 T cells and then in hRPCS derived from human embryonic stem cells. The candidate region (RAX-3258 bp) showed the highest EGFP expression in hRPCs. This reporter construct can be used for in vitro monitoring of hRPC identity and verification of an efficient culture medium for maintenance of these cells. Conclusions Furthermore, our findings provide a platform for better insight into regulatory regions of human RAX gene and molecular mechanisms underlying its vital functions in retina development.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xueqing Chen ◽  
Mark M. Emerson

AbstractNotch signaling is required to repress the formation of vertebrate cone photoreceptors and to maintain the proliferative potential of multipotent retinal progenitor cells. However, the mechanism by which Notch signaling controls these processes is unknown. Recently, restricted retinal progenitor cells with limited proliferation capacity and that preferentially generate cone photoreceptors have been identified. Thus, there are several potential steps during cone genesis that Notch signaling could act. Here we use cell type specific cis-regulatory elements to localize the primary role of Notch signaling in cone genesis to the formation of restricted retinal progenitor cells from multipotent retinal progenitor cells. Localized inhibition of Notch signaling in restricted progenitor cells does not alter the number of cones derived from these cells. Cell cycle promotion is not a primary effect of Notch signaling but an indirect effect on progenitor cell state transitions that leads to depletion of the multipotent progenitor cell population. Taken together, this suggests that the role of Notch signaling in cone photoreceptor formation and proliferation are both mediated by a localized function of Notch in multipotent retinal progenitor cells to repress the formation of restricted progenitor cells.


2021 ◽  
Vol 62 (3) ◽  
pp. 31
Author(s):  
Lorena Teixeira Frasson ◽  
Barbara Dalmaso ◽  
Priscilla Sayami Akamine ◽  
Edna Teruko Kimura ◽  
Dânia Emi Hamassaki ◽  
...  

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