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

ABSTRACT: 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.

SUBMITTER: Park SE

PROVIDER: S-EPMC7988745 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Park Sang Eon SE Kim Hyeong Seop HS Kwon Soo Jin SJ Kim Min-Jeong MJ Choi Suk-Joo SJ Oh Soo-Young SY Ryu Gyu Ha GH Jeon Hong Bae HB Na Duk L DL Chang Jong Wook JW

Stem cells international 20210316

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 c ...[more]

PMID: 33815510

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Project description:BackgroundIn recent years, the utilization of stem cell therapy and cell sheet technology has emerged as a promising approach for addressing spinal cord injury (SCI). However, the most appropriate cell type and mechanism of action remain unclear at this time. This study sought to develop an SCI rat model and evaluate the therapeutic effects of human umbilical cord mesenchymal stem cell (hUC-MSC) sheets in this model. Furthermore, the mechanisms underlying the vascular repair effect of hUC-MSC sheets following SCI were investigated.MethodsA temperature-responsive cell culture method was employed for the preparation of hUC-MSC sheets. The extracellular matrix (ECM) produced by hUC-MSCs serves two distinct yet interrelated purposes. Firstly, it acts as a biologically active scaffold for transplanted cells, facilitating their attachment and proliferation. Secondly, it provides mechanical support and bridges spinal cord stumps, thereby facilitating the restoration of spinal cord function. The formation of the cavity within the spinal cord was evaluated using the Hematoxylin and Eosin (H&E) staining method. Subsequently, endothelial cells were cultivated with the conditioned medium (CM) obtained from hUC-MSCs or hUC-MSC sheets. The pro-angiogenic impact of the conditioned medium of hUC-MSCs (MSC-CM) and the conditioned medium of hUC-MSC sheets (CS-CM) was evaluated through the utilization of the CCK-8 assay, endothelial wound healing assay, and tube formation assay in an in vitro context. The development of glial scars, blood vessels, neurons, and axons in hUC-MSCs and hUC-MSC sheets was assessed through immunofluorescence staining.ResultsIn comparison to hUC-MSCs, hUC-MSC sheets demonstrated a more pronounced capacity to facilitate vascular formation and induce the regeneration of newborn neurons at the SCI site, while also reducing glial scar formation and significantly enhancing motor function in SCI rats. Notably, under identical conditions, the formation of cell sheets has been associated with a paracrine increase in the ability of the cells themselves to secrete pro-angiogenic growth factors. During the course of the experiment, it was observed that the secretion of uPAR was the most pronounced among the pro-angiogenic factors present in MSC-CM and CS-CM. This finding was subsequently corroborated in subsequent experiments, wherein uPAR was demonstrated to promote angiogenesis via the PI3K/Akt signaling pathway.ConclusionThe creation of cell sheets not only significantly enhances the biological function of hUC-MSCs but also effectively retains the cells locally in spinal cord injury. Therefore, the transplantation of hUC-MSC sheets can maximize the function of hUC-MSCs, greatly reducing glial scar formation, enhancing vascular formation, and promoting the regeneration of neurons and axons. Additionally, the research findings prove that hUC-MSC sheets activate the PI3K/Akt signaling pathway through uPAR secretion to enhance angiogenesis. The transfer of the entire extracellular matrix by hUC-MSC sheets, in the absence of the introduction of additional exogenous or synthetic biomaterials, serves to further augment their potential for clinical application.

Project description:Purpose: Iron oxide based magnetic nanoparticles (MNP) are versatile tools in biology and medicine. Adipose derived mesenchymal stem cells (ADSC) and Wharton Jelly mesenchymal stem cells (WJMSC) are currently tested in different strategies for regenerative regenerative medicine (RM) purposes. Their superiority compared to other mesenchymal stem cell consists in larger availability, and superior proliferative and differentiation potential. Magnetic field (MF) exposure of MNP-loaded ADSC has been proposed as a method to deliver mechanical stimulation for increasing conversion to musculoskeletal lineages. In this study, we investigated comparatively chondrogenic conversion of ADSC-MNP and WJMSC with or without MF exposure in order to identify the most appropriate cell source and differentiation protocol for future cartilage engineering strategies. Methods: Human primary ADSC and WJMSC from various donors were loaded with proprietary uncoated MNP. The in vitro effect on proliferation and cellular senescence (beta galactosidase assay) in long term culture was assessed. In vitro chondrogenic differentiation in pellet culture system, with or without MF exposure, was assessed using pellet histology (Safranin O staining) as well as quantitative evaluation of glycosaminoglycan (GAG) deposition per cell. Results: ADSC-MNP complexes displayed superior proliferative capability and decreased senescence after long term (28 days) culture in vitro compared to non-loaded ADSC and to WJMSC-MNP. Significant increase in chondrogenesis conversion in terms of GAG/cell ratio could be observed in ADSC-MNP. MF exposure increased glycosaminoglycan deposition in MNP-loaded ADSC, but not in WJMSC. Conclusion: ADSC-MNP display decreased cellular senescence and superior chondrogenic capability in vitro compared to non-loaded cells as well as to WJMSC-MNP. MF exposure further increases ADSC-MNP chondrogenesis in ADSC, but not in WJMSC. Loading ADSC with MNP can derive a successful procedure for obtaining improved chondrogenesis in ADSC. Further in vivo studies are needed to confirm the utility of ADSC-MNP complexes for cartilage engineering.

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

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

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