Neuroprotective effects of bone marrow Sca-1+ cells against age-related retinal degeneration in OPTN E50K mice

AbstractGlaucoma is characterized by retinal ganglion cell (RGC) death, the underlying mechanisms of which are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal-tension glaucoma (NTG), which directly affects RGCs in the absence of high intraocular pressure and causes severe glaucomatous symptoms in patients. Bone marrow (BM) stem cells have been demonstrated to play a key role in regenerating damaged tissue during ageing and disease through their trophic effects and homing capability. Here, we separated BM stem cells into Sca-1+ and Sca-1- cells and transplanted them into lethally irradiated aged OPTN E50K mice to generate Sca-1+ and Sca-1− chimaeras, respectively. After 3 months of BM repopulation, we investigated whether Sca-1+ cells maximized the regenerative effects in the retinas of NTG model mice with the OPTN E50K mutation. We found that the OPTN E50K mutation aggravated age-related deficiency of neurotrophic factors in both retinas and BM during NTG development, leading to retinal degeneration and BM dysfunction. Sca-1+ cells from young healthy mice had greater paracrine trophic effects than Sca-1− cells and Sca-1+ cells from young OPTN E50K mice. In addition, Sca-1+ chimaeras demonstrated better visual functions than Sca-1− chimaeras and untreated OPTN E50K mice. More Sca-1+ cells than Sca-1− cells were recruited to repair damaged retinas and reverse visual impairment in NTG resulting from high expression levels of neurotrophic factors. These findings indicated that the Sca-1+ cells from young, healthy mice may have exhibited an enhanced ability to repair retinal degeneration in NTG because of their excellent neurotrophic capability.

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Dosage and Passage Dependent Neuroprotective Effects of Exosomes Derived from Rat Bone Marrow Mesenchymal Stem Cells: An In Vitro Analysis

Current Gene Therapy ◽

10.2174/1566523218666180125091952 ◽

2018 ◽

Vol 18 ◽

Cited By ~ 2

Author(s):

Chaitra Venugopal ◽

Christopher Shamir ◽

Sivapriya Senthilkumar ◽

Janitri Venkatachala Babu ◽

Peedikayil Kurien Sonu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Neuroprotective Effects ◽

Marrow Mesenchymal Stem Cells ◽

Vitro Analysis ◽

In Vitro Analysis ◽

Rat Bone

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Subpopulations of Bone Marrow Mesenchymal Stem Cells Exhibit Differential Effects in Delaying Retinal Degeneration

Current Molecular Medicine ◽

10.2174/1566524016666160607090953 ◽

2016 ◽

Vol 16 (6) ◽

pp. 567-581 ◽

Cited By ~ 7

Author(s):

P. Li ◽

H. Tian ◽

Z. Li ◽

L. Wang ◽

F. Gao ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Retinal Degeneration ◽

Differential Effects ◽

Marrow Mesenchymal Stem Cells

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Neuroprotective Effects of Bone Marrow Mesenchymal Stem Cells on Bilateral Common Carotid Arteries Occlusion Model of Cerebral Ischemia in Rat

Behavioural Neurology ◽

10.1155/2016/2964712 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Bagher Pourheydar ◽

Sara Soleimani Asl ◽

Mostafa Azimzadeh ◽

Adel Rezaei Moghadam ◽

Asghar Marzban ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cerebral Ischemia ◽

Functional Recovery ◽

Carotid Arteries ◽

Ischemia Reperfusion ◽

Neuroprotective Effects ◽

Marrow Mesenchymal Stem Cells ◽

Common Carotid Arteries

Cell therapy is the most advanced treatment of the cerebral ischemia, nowadays. Herein, we discuss the neuroprotective effects of bone marrow mesenchymal stem cells (BMSCs) on rat hippocampal cells following intravenous injection of these cells in an ischemia-reperfusion model. Adult male Wistar rats were divided into 5 groups: control, sham (surgery without blockage of common carotid arteries), ischemia (common carotid arteries were blocked for 30 min prior to reperfusion), vehicle (7 days after ischemia PBS was injected via the tail vein), and treatment (injections of BMSC into the tail veins 7 days after ischemia). We performed neuromuscular and vestibulomotor function tests to assess behavioral function and, finally, brains were subjected to hematoxylin and eosin (H&E), anti-Brdu immunohistochemistry, and TUNEL staining. The ischemia group had severe apoptosis. The group treated with BMSCs had a lower mortality rate and also had significant improvement in functional recovery (P<0.001). Ischemia-reperfusion for 30 min causes damage and extensive neuronal death in the hippocampus, especially in CA1 and CA3 regions, leading to several functional and neurological deficits. In conclusion, intravenous injection of BMSCs can significantly decrease the number of apoptotic neurons and significantly improve functional recovery, which may be a beneficial treatment method for ischemic injuries.

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Bone marrow mesenchymal stem cells overexpressing hepatocyte growth factor ameliorate hypoxic–ischemic brain damage in neonatal rats

Translational Neuroscience ◽

10.1515/tnsci-2020-0204 ◽

2021 ◽

Vol 12 (1) ◽

pp. 561-572

Author(s):

Wen Zeng ◽

Yu Wang ◽

Yufeng Xi ◽

Guoqing Wei ◽

Rong Ju

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Neuroprotective Effects ◽

Western Blots ◽

Ischemic Brain ◽

Marrow Mesenchymal Stem Cells ◽

Hepatocyte Growth

Abstract Objectives Hypoxic–ischemic brain damage (HIBD) is a major cause of brain injury in neonates. Bone marrow mesenchymal stem cells (BMSCs) show therapeutic potential for HIBD, and genetic modification may enhance their neuroprotective effects. The goal of this study was to investigate the neuroprotective effects of hepatocyte growth factor (HGF)-overexpressing BMSCs (BMSCs-HGF) against HIBD and their underlying mechanisms. Methods: BMSCs were transfected with HGF using adenoviral vectors. HIBD models were established and then BMSCs were transplanted into the brains of HIBD rats via intraventricular injection. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to measure cerebral infarction volumes. In vitro, primary cultured cortical neurons were co-cultured with BMSCs in a Transwell plate system. Oxygen–glucose deprivation (OGD) was applied to imitate hypoxic–ischemic insult, and PD98059 was added to the culture medium to block the phosphorylation of extracellular signal-regulated kinase (ERK). Cell apoptosis was determined using TUNEL staining. The expression of HGF was measured by immunofluorescence, real-time quantitative PCR (RT-qPCR), and western blots. The expression of phosphorylated ERK (p-ERK) and B-cell lymphoma-2 (Bcl-2) was measured by western blots. Results HGF-gene transfection promoted BMSC proliferation. Moreover, BMSCs-HGF decreased HIBD-induced cerebral infarction volumes and enhanced the protective effects of the BMSCs against HIBD. BMSCs-HGF also increased expression of HGF, p-ERK, and Bcl-2 in brain tissues. In vitro, BMSC-HGF protected neurons against OGD-induced apoptosis. Inhibition of ERK phosphorylation abolished the neuroprotective effect of BMSCs-HGF against OGD. Conclusions BMSCs-HGF is a potential treatment for HIBD and that the ERK/Bcl-2 pathway is involved in the underlying neuroprotective mechanism.

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Overexpression of MiR-183/96/182 Triggers Retina-Like Fate in Human Bone Marrow-Derived Mesenchymal Stem Cells (hBMSCs) in Culture

Journal of Ophthalmology ◽

10.1155/2019/2454362 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9

Author(s):

Mohammad-Reza Mahmoudian-Sani ◽

Fatemeh Forouzanfar ◽

Samira Asgharzade ◽

Nilufar Ghorbani

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Retinal Degeneration ◽

Photoreceptor Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Efficient Treatment ◽

Qrt Pcr

Retinal degeneration is considered as a condition ensued by different blinding disorders such as retinitis pigmentosa, age-related macular degeneration, and diabetic retinopathy, which can cause loss of photoreceptor cells and also lead to significant vision deficiencies. Although there is no efficient treatment in this domain, transplantation of stem cells has been regarded as a therapeutic approach for retinal degeneration. Thus, the purpose of this study was to analyze the potential of human bone marrow-derived mesenchymal stem cells (hBMSCs) to differentiate into photoreceptor cells via transfection of microRNA (miRNA) in vitro for regenerative medicine purposes. To this end, miR-183/96/182 cluster was transfected into hBMSCs; then, qRT-PCR was performed to measure the expression levels of miR-183/96/182 cluster and some retina-specific neuronal genes such as OTX2, NRL, PKCα, and recoverin. CRX and rhodopsin (RHO) levels were also measured through qRT-PCR and immunocytochemistry, and subsequently, cellular change morphology was detected. The findings showed no changes in the morphology of the given cells, and the expression of the neuroretinal genes such as OTX2, NRL, and PKCα. Moreover, recoverin was upregulated upon miR-183/-96/-182 overexpression in cultured hBMSCs. Ectopic overexpression of the miR-183 cluster could further increase the expression of CRX and RHO at the messenger RNA (mRNA) and protein levels. Furthermore, the data indicated that the miR-183 cluster could serve as a crucial function in photoreceptor cell differentiation. In fact, miRNAs could be assumed as potential targets to exploit silent neuronal differentiation. Ultimately, it was suggested that in vitro overexpression of miR-183 cluster could trigger reprogramming of the hBMSCs to retinal neuron fate, especially photoreceptor cells.

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AGE-ASSOCIATED INCREASE IN KYNURENINE INHIBITS AUTOPHAGY AND PROMOTES SENESCENCE IN BONE MARROW STEM CELLS

Innovation in Aging ◽

10.1093/geroni/igz038.3469 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S956-S956

Author(s):

Dmitry Kondrikov ◽

Ahmed Elmansi ◽

Xing-ming Shi ◽

Sadanand Fulzele ◽

Meghan mcGee-Lawrence ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Cell Lines ◽

Free Radical Oxidation ◽

Autophagic Flux ◽

Galactosidase Activity ◽

Activity Increase ◽

Age Related ◽

Old Mice

Abstract Aging is characterized by progressive decline of tissue functionality and age-related accumulation of cellular and molecular damage leading to multiple pathological conditions including osteoporosis and increased fracture rates. Bone marrow mesenchymal stem cells (BMSCs) play an essential role in bone development and regeneration with their ability to undergo differentiation into osteogenic, chondrogenic, myogenic, and adipogenic cell lines cell lines. Proliferation rate of MSC is declined with ages leading to misbalance between bone resorption and osteogenesis. A recently identified age-related change in bone and bone marrow is an accumulation of tryptophan metabolite, kynurenine (KYN), catalyzed by indoleamine-2,3-dioxygenase (IDO) or free-radical oxidation. We previously reported that KYN suppresses autophagy in BMSC. We now investigated the effect of KYN on BMSC cellular function. In vitro treatment of murine BMSC isolated from 18 month old mice with kynurenine disrupted autophagy suppressing autophagic flux. KYN treatment also induces senescence in BMSC marked by increase in SA-beta-galactosidase activity as well as, increased expression of senescence marker p21. Inhibition of Aryl Hydrocarbon Receptor (AhR) by AhR inhibitors significantly reduced β-galactosidase activity increase and blocked p21 expression elevation suggesting that KYN induces senescence in BMSC through the AhR pathway. Interestingly, KYN treatment failed to up-regulate beta-gal activity in BMSC isolated from 6 month-old mice suggesting that KYN induction of senescence maybe potentiated with aging. Together those data support the idea that KYN shifts the homeostatic balance of BMSC during prolonged stress or in aging through downregulating survival autophagic pathway in favor of driving BMSCs to senescence.

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Saffron (Crocus sativus L.) in Ocular Diseases: A Narrative Review of the Existing Evidence from Clinical Studies

Nutrients ◽

10.3390/nu11030649 ◽

2019 ◽

Vol 11 (3) ◽

pp. 649 ◽

Cited By ~ 15

Author(s):

Rebekka Heitmar ◽

James Brown ◽

Ioannis Kyrou

Keyword(s):

Clinical Studies ◽

Wide Spectrum ◽

Narrative Review ◽

Age Related Macular Degeneration ◽

Crocus Sativus ◽

Ocular Diseases ◽

Neuroprotective Effects ◽

Age Related ◽

Underlying Mechanisms ◽

Crocus Sativus L

Saffron (Crocus sativus L.) and its main constituents, i.e., crocin and crocetin, are natural carotenoid compounds, which have been reported to possess a wide spectrum of properties and induce pleiotropic anti-inflammatory, anti-oxidative, and neuroprotective effects. An increasing number of experimental, animal, and human studies have investigated the effects and mechanistic pathways of these compounds in order to assess their potential therapeutic use in ocular diseases (e.g., in age related macular degeneration, glaucoma, and diabetic maculopathy). This narrative review presents the key findings of published clinical studies that examined the effects of saffron and/or its constituents in the context of ocular disease, as well as an overview of the proposed underlying mechanisms mediating these effects.

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