Exposure of Mesenchymal Stem Cells to an Alzheimer’s Disease Environment Enhances Therapeutic Effects

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of Alzheimer’s disease (AD). Previous studies suggested that the coculture of human MSCs with AD in an in vitro model reduced the expression of amyloid-beta 42 (Aβ42) in the medium as well as the overexpression of amyloid-beta- (Aβ-) degrading enzymes such as neprilysin (NEP). We focused on the role of primed MSCs (human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) exposed to an AD cell line via a coculture system) in reducing the levels of Aβ and inhibiting cell death. We demonstrated that mouse groups treated with naïve MSCs and primed MSCs showed significant reductions in cell death, ubiquitin conjugate levels, and Aβ levels, but the effects were greater in primed MSCs. Also, mRNA sequencing data analysis indicated that high levels of TGF-β induced primed-MSCs. Furthermore, treatment with TGF-β reduced Aβ expression in an AD transgenic mouse model. These results highlighted AD environmental preconditioning is a promising strategy to reduce cell death and ubiquitin conjugate levels and maintain the stemness of MSCs. Further, these data suggest that human WJ-MSCs exposed to an AD environment may represent a promising and novel therapy for AD.

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Exposure of Mesenchymal Stem Cells to an Alzheimer’s Disease Environment Enhances Therapeutic Effects

10.21203/rs.3.rs-89815/v1 ◽

2020 ◽

Author(s):

Sang eon Park ◽

Hyeong Seop Kim ◽

Soo Jin Kwon ◽

Min-Jeong Kim ◽

Suk-joo Choi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Cell Death ◽

Mesenchymal Stem Cells ◽

Amyloid Beta ◽

Therapeutic Effects ◽

Human Mscs ◽

Sequencing Data ◽

Ubiquitin Conjugate

Abstract BackgroundMesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of Alzheimer’s disease (AD). Previous studies suggested that the co-culture of human MSCs with AD in an in vitro model reduced the expression of amyloid-beta 42 (Aβ42) in the medium as well as the overexpression of amyloid-beta (Aβ )-degrading enzymes such as neprilysin (NEP).MethodsIn this study, we focused on the role of primed MSCs (human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exposed to an AD cell line via a co-culture system) in reducing the levels of Aβ and inhibiting cell death. ResultsWe demonstrated that mouse groups treated with naïve MSCs and primed MSCs showed significant reductions in cell death, ubiquitin conjugate levels, and Aβ levels, but the effects were greater in primed MSCs. Also, mRNA sequencing data analysis indicated that high levels of TGF-β induced primed-MSCs. Furthermore, treatment with TGF-β reduced Aβ expression in an AD transgenic mouse model. ConclusionAD environmental preconditioning is a promising strategy to reduce cell death and ubiquitin conjugate levels and maintain the stemness of MSCs. Further, these data suggest that human WJ-MSCs exposed to an AD environment may represent a promising and novel therapy for AD.

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Therapeutic effects of melatonin-treated bone marrow mesenchymal stem cells (BMSC) in a rat model of Alzheimer's disease

Journal of Chemical Neuroanatomy ◽

10.1016/j.jchemneu.2020.101804 ◽

2020 ◽

Vol 108 ◽

pp. 101804

Author(s):

Mahdi Ramezani ◽

Alireza Komaki ◽

Nasrin Hashemi-Firouzi ◽

Keywan Mortezaee ◽

Nafiseh Faraji ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Rat Model ◽

Therapeutic Effects ◽

Model Of Alzheimer’S Disease ◽

Marrow Mesenchymal Stem Cells

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Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease

Cellular Physiology and Biochemistry ◽

10.1159/000430356 ◽

2015 ◽

Vol 37 (1) ◽

pp. 321-330 ◽

Cited By ~ 16

Author(s):

Zhen Liu ◽

Cunfu Wang ◽

Xiao Wang ◽

Shunliang Xu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Murine Model ◽

Social Recognition ◽

Saline Control ◽

Mouse Bone Marrow ◽

Therapeutic Effects ◽

Mrna Levels

Background/Aims: Alzheimer's disease (AD) is one of the most common dementias among aged people, and is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits. So far, this is no cure for AD. A therapeutic effect of transplantation of mesenchymal stem cells (MSCs) into murine model of AD has been reported, but remains to be further improved. Brn-4 is a transcription factor that plays a critical role in neuronal development, whereas the effects of Brn-4 overexpression in transplanted MSCs on AD are unknown. Methods: MSCs were isolated from mouse bone marrow and induced to overexpress antisense of miRNA-937 (as-miR-937) through adeno-associated virus (AAV)-mediated transduction, and purified by flow cytometry based on expression of a GFP co-transgene in the cells. The Brn-4 levels in mouse MSCs were examined in miR-937-modified MSCs by RT-qPCR and by Western blot. These miR-937-modified MSCs were then transplanted into an APP/PS1 transgenic AD model in mice. The effects of saline control, MSCs and asmiR-937 MSCs on AD mice were examined by deposition of amyloid-beta peptide aggregates (Aβ), social recognition test (SR), Plus-Maze Discriminative Avoidance Task (PM-DAT) and the levels of Brain-derived neurotrophic factor (BDNF) in the mouse brain. Results: MSCs expressed high levels of Brn-4 transcripts but low levels of Brn-4 protein. Poor protein vs mRNA levels of Brn-4 in MSCs appeared to result from the presence of high levels of miR-937 in MSCs. miR-937 inhibited translation of Brn-4 mRNA through binding to the 3'-UTR of the Brn-4 mRNA in MSCs. Expression of as-miR-937 significantly increased Brn-4 protein levels in MSCs. Transplantation of as-miR-937-expressing MSCs significantly reduced the deposition of Aβ, increased the levels of BDNF, and significantly improved the appearance in SR and PM-DAT in AD mice. Conclusion: Overexpression of as-miR-937 in MSCs may substantially improve the therapeutic effects of MSCs on AD, possibly through augmenting Brn-4 levels in MSCs.

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