Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury
Abstract Background Retinal and/or optic nerve injury is one of the leading causes of blindness due to retinal ganglion cell (RGC) degeneration. There have been extensive efforts to suppress this neurodegeneration. Various somatic tissue-derived mesenchymal stem cells (MSCs) demonstrated significant...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-020-01702-x |
| _version_ | 1819226339934208000 |
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| author | Seyedeh-Zahra Seyedrazizadeh Sara Poosti Abdoreza Nazari Mehdi Alikhani Faezeh Shekari Farzad Pakdel Koorosh Shahpasand Leila Satarian Hossein Baharvand |
| author_facet | Seyedeh-Zahra Seyedrazizadeh Sara Poosti Abdoreza Nazari Mehdi Alikhani Faezeh Shekari Farzad Pakdel Koorosh Shahpasand Leila Satarian Hossein Baharvand |
| author_sort | Seyedeh-Zahra Seyedrazizadeh |
| collection | DOAJ |
| description | Abstract Background Retinal and/or optic nerve injury is one of the leading causes of blindness due to retinal ganglion cell (RGC) degeneration. There have been extensive efforts to suppress this neurodegeneration. Various somatic tissue-derived mesenchymal stem cells (MSCs) demonstrated significant neuroprotective and axogenic effects on RGCs. An alternative source of MSCs could be human embryonic stem cells (ES-MSCs), which proliferate faster, express lower levels of inflammatory cytokines, and are capable of immune modulation. It has been demonstrated that MSCs secrete factors or extracellular vesicles that may heal the injury. However, possible therapeutic effects and underlying mechanism of human ES-MSC extracellular vesicles (EVs) on optic nerve injury have not been assessed. Methods EVs were isolated from human ES-MSCs. Then, ES-MSC EV was applied to an optic nerve crush (ONC) mouse model. Immunohistofluorescence, retro- and anterograde tracing of RGCs, Western blot, tauopathy in RGCs, and function assessments were performed during 2-month post-treatment to evaluate ONC improvement and underlying mechanism of human ES-MSC EV in in vivo. Results We found that the ES-MSC EV significantly improved Brn3a+ RGCs survival and retro- and anterograde tracing of RGCs, while preventing retinal nerve fiber layer (RNFL) degenerative thinning compared to the vehicle group. The EVs also significantly promoted GAP43+ axon counts in the optic nerve and improved cognitive visual behavior. Furthermore, cis p-tau, a central mediator of neurodegeneration in the injured RGCs, is detectable after the ONC at the early stages demonstrated tauopathy in RGCs. Notably, after EV treatment cis p-tau was downregulated. Conclusions Our findings propose that human ES-MSC EVs, as an off-the-shelf and cell-free product, may have profound clinical implications in treating injured RGCs and degenerative ocular disease. Moreover, the possible mechanisms of human ES-MSC EV are related to the rescue of tauopathy process of RGC degeneration. |
| first_indexed | 2024-12-23T10:23:56Z |
| format | Article |
| id | doaj.art-7c8690429f4b438c891ba76042701aa6 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-23T10:23:56Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-7c8690429f4b438c891ba76042701aa62022-12-21T17:50:37ZengBMCStem Cell Research & Therapy1757-65122020-05-0111111310.1186/s13287-020-01702-xExtracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injurySeyedeh-Zahra Seyedrazizadeh0Sara Poosti1Abdoreza Nazari2Mehdi Alikhani3Faezeh Shekari4Farzad Pakdel5Koorosh Shahpasand6Leila Satarian7Hossein Baharvand8Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECROphthalmology Department, Eye Research Center, Tehran University of Medical SciencesDepartment of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRDepartment of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECRAbstract Background Retinal and/or optic nerve injury is one of the leading causes of blindness due to retinal ganglion cell (RGC) degeneration. There have been extensive efforts to suppress this neurodegeneration. Various somatic tissue-derived mesenchymal stem cells (MSCs) demonstrated significant neuroprotective and axogenic effects on RGCs. An alternative source of MSCs could be human embryonic stem cells (ES-MSCs), which proliferate faster, express lower levels of inflammatory cytokines, and are capable of immune modulation. It has been demonstrated that MSCs secrete factors or extracellular vesicles that may heal the injury. However, possible therapeutic effects and underlying mechanism of human ES-MSC extracellular vesicles (EVs) on optic nerve injury have not been assessed. Methods EVs were isolated from human ES-MSCs. Then, ES-MSC EV was applied to an optic nerve crush (ONC) mouse model. Immunohistofluorescence, retro- and anterograde tracing of RGCs, Western blot, tauopathy in RGCs, and function assessments were performed during 2-month post-treatment to evaluate ONC improvement and underlying mechanism of human ES-MSC EV in in vivo. Results We found that the ES-MSC EV significantly improved Brn3a+ RGCs survival and retro- and anterograde tracing of RGCs, while preventing retinal nerve fiber layer (RNFL) degenerative thinning compared to the vehicle group. The EVs also significantly promoted GAP43+ axon counts in the optic nerve and improved cognitive visual behavior. Furthermore, cis p-tau, a central mediator of neurodegeneration in the injured RGCs, is detectable after the ONC at the early stages demonstrated tauopathy in RGCs. Notably, after EV treatment cis p-tau was downregulated. Conclusions Our findings propose that human ES-MSC EVs, as an off-the-shelf and cell-free product, may have profound clinical implications in treating injured RGCs and degenerative ocular disease. Moreover, the possible mechanisms of human ES-MSC EV are related to the rescue of tauopathy process of RGC degeneration.http://link.springer.com/article/10.1186/s13287-020-01702-xHuman embryonic stem cellsMesenchymal stem cellsOptic nerve crushExtracellular vesicleCis P- tau |
| spellingShingle | Seyedeh-Zahra Seyedrazizadeh Sara Poosti Abdoreza Nazari Mehdi Alikhani Faezeh Shekari Farzad Pakdel Koorosh Shahpasand Leila Satarian Hossein Baharvand Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury Stem Cell Research & Therapy Human embryonic stem cells Mesenchymal stem cells Optic nerve crush Extracellular vesicle Cis P- tau |
| title | Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| title_full | Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| title_fullStr | Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| title_full_unstemmed | Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| title_short | Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| title_sort | extracellular vesicles derived from human es mscs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury |
| topic | Human embryonic stem cells Mesenchymal stem cells Optic nerve crush Extracellular vesicle Cis P- tau |
| url | http://link.springer.com/article/10.1186/s13287-020-01702-x |
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