Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

Pinho, Andreia G.; Cibrão, Jorge R.; Silva, Nuno; Monteiro, Susana; Salgado, António J.

doi:10.3390/ph13020031

Cited by 60 publications

(60 citation statements)

References 150 publications

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“…Then, culture media were removed, and the cells incubated for 24 h with an equivalent volume of the secretome derived from untreated astrocytes and from pre-miR-146a and VS treated cells. Secretome contains soluble factors and vesicular fractions as sEVs, essentially containing miRNAs (Pinho et al, 2020). We showed that sEVs were preferentially collected by microglia than by MNs, when in coculture (Pinto et al, 2017).…”

Section: N9-microglia Cell Culture and Treatment With Astrocyte-derived Secretome And Sevsmentioning

confidence: 80%

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons

Barbosa

Gomes

Sequeira

et al. 2021

Front. Cell Dev. Biol.

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Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca2+ overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.

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Section: N9-microglia Cell Culture and Treatment With Astrocyte-derived Secretome And Sevsmentioning

confidence: 80%

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons

Barbosa

Gomes

Sequeira

et al. 2021

Front. Cell Dev. Biol.

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“…Although the mechanism of MSCs’ action has not been completely understood, numerous studies have demonstrated the extracellular secreted factors and vesicles—their secretome as their “active ingredients” for regenerative and cytoprotective effects, and immunomodulatory property of the MSC-based therapy [ 57 , 58 ]. MSC-derived soluble factors and vehicle-bound substances (secretome or conditional medium) from different sources consist of IFN-γ, IL-17, IL-10, IL-6, TGF-β, IL-2, TNF-α, and HLA (for immunomodulation), and GDNF, FGF, IGF, BDNF, PEGF, PDGF, miRNAs, VEGF, and MMPs (for cell survival/growth and tissue remodeling) [ 59 – 61 ]. The composition of the secretome of MSCs appears to vary significantly, depending on the age of the host and niches where the cells are collected [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats

Zong

Guan

et al. 2021

Stem Cell Res Ther

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Background A long-term of peritoneal dialysis (PD) using a hypertonic PD solution (PDS) leads to patient’s peritoneal membrane (PM) injury, resulting in ultrafiltration failure (UFF) and PD drop-out. Our previous study shows that PD effluent-derived mesenchymal stromal cells (pMSCs) prevent the PM injury in normal rats after repeated exposure of the peritoneal cavity to a PDS. This study was designed to compare the cytoprotection between pMSCs and umbilical cord-derived MSCs (UC-MSCs) in the treatment of both PM and kidney injury in uremic rats with chronic PD. Methods 5/6 nephrectomized (5/6Nx) Sprague Dawley rats were intraperitoneally (IP) injected Dianeal (4.25% dextrose, 10 mL/rat/day) and were treated with pMSCs or umbilical cord (UC)-MSCs (approximately 2 × 106/rat/week, IP). Ultrafiltration was determined by IP injection of 30 mL of Dianeal (4.25% dextrose) with 1.5-h dewell time, and kidney failure by serum creatinine (SCr) and blood urea nitrogen (BUN). The structure of the PM and kidneys was assessed using histology. Gene expression was examined using quantitative reverse transcription PCR, and protein levels using flow cytometric and Western blot analyses. Results We showed a slight difference in the morphology between pMSCs and UC-MSCs in plastic dishes, and significantly higher expression levels of stemness-related genes (NANOG, OCT4, SOX2, CCNA2, RAD21, and EXO1) and MSCs surface markers (CD29, CD44, CD90 and CD105) in UC-MSCs than those in pMSCs, but no difference in the differentiation to chondrocytes, osteocytes or adipocytes. pMSC treatment was more effective than UC-MSCs in the protection of the MP and remnant kidneys in 5/6Nx rats from PDS-induced injury, which was associated with higher resistance of pMSCs than UC-MSCs to uremic toxins in culture, and more reduction of peritoneal mesothelial cell death by the secretome from pMSCs than from UC-MSCs in response to PDS exposure. The secretome from both pMSCs and UC-MSCs similarly inactivated NOS2 in activated THP1 cells. Conclusions As compared to UC-MSCs, pMSCs may more potently prevent PDS-induced PM and remnant kidney injury in this uremic rat model of chronic PD, suggesting that autotransplantation of ex vivo-expanded pMSCs may become a promising therapy for UFF and deterioration of remnant kidney function in PD patients.

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“…MSCs are pluripotent, non-hematopoietic stem cells with the ability to differentiate into a diverse number of cell lineages, including chondrocytes, osteoblasts, and neuron-like cells ( Uccelli et al, 2006 ; Williams and Keating, 2008 ). They can be isolated from almost all tissues in mammals including bone marrow (BM), adipose tissue or other tissues ( Pinho et al, 2020 ) and are easy to culture and effectively expand. BM-MSCs are the most common, while in recent years adipose-derived MSCs have become increasingly popular due to their easy availability and high yield ( Faghih et al, 2017 ; Perteghella et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell-Based Therapy for Stroke: Current Understanding and Challenges

Liu

Shi

et al. 2021

Front. Cell. Neurosci.

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Stroke, the most prevalent cerebrovascular disease, causes serious loss of neurological function and is the leading cause of morbidity and mortality worldwide. Despite advances in pharmacological and surgical therapy, treatment for functional rehabilitation following stroke is limited with a consequent serious impact on quality of life. Over the past decades, mesenchymal stem cell (MSCs)-based therapy has emerged as a novel strategy for various diseases including stroke due to their unique properties that include easy isolation, multipotent differentiation potential and strong paracrine capacity. Although MSCs have shown promising results in the treatment of stroke, there remain many challenges to overcome prior to their therapeutic application. In this review, we focus on the following issues: the scientific data from preclinical studies and clinical trials of MSCs in the treatment of stroke; the potential mechanisms underlying MSC-based therapy for stroke; the challenges related to the timing and delivery of MSCs and MSC senescence.

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Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

Cited by 60 publications

References 150 publications

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons

Recovery of Depleted miR-146a in ALS Cortical Astrocytes Reverts Cell Aberrancies and Prevents Paracrine Pathogenicity on Microglia and Motor Neurons

Comparison of mesenchymal stromal cells from peritoneal dialysis effluent with those from umbilical cords: characteristics and therapeutic effects on chronic peritoneal dialysis in uremic rats

Mesenchymal Stem Cell-Based Therapy for Stroke: Current Understanding and Challenges

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