Crohn's Disease Disturbs the Immune Properties of Human Adipose-Derived Stem Cells Related to Inflammasome Activation

Serena, Carolina; Keiran, Noelia; Madeira, Ana; Maymó-Masip, Elsa; Ejarque, Miriam; Terrón-Puig, Margarida; Espín, Eloy; Martí, Marc; Borruel, Natalia; Guarner, Francisco; Menacho, Margarita; Zorzano, António; Millán, Mónica; Fernández‐Veledo, Sonia; Vendrell, Joan

doi:10.1016/j.stemcr.2017.07.014

Cited by 53 publications

(65 citation statements)

References 42 publications

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“…We observed that the expression of almost all of the genes tested was normalized to control levels in hASCs isolated from patients with inactive disease, indicating that immune system genes affected by methylation marks were for the most part partially restored in patients during episodes of remission. The exception to this was TNFA, whose expression remained high in patients during remission, which is in agreement with previous data [18].…”

Section: Immune Systemsupporting

confidence: 93%

“…We found statistically significant differences in 18,253 CpGs between CD-and control-hASCs. To specifically evaluate the methylation patterns and the preferential genome location, we segmented all significant differentially methylated positions (DMPs) with a p value < 1 × 10 −4 into the following eight categories according to the Illumina annotations: transcription start site (TSS) 1500, TSS 200 (indicating the number of bases upstream), 5′ untranslated region (UTR), 1st exon, ExonBnd (exon boundary), gene body, 3′ UTR, and no gene location ( Fig.…”

Section: Differentially Methylated Positions In Adipose Stem Cells Ismentioning

confidence: 69%

“…For example, hASCs administered to the circulation have the ability to home to inflamed/injured tissues [14,15]. Of note, some metabolic stress-induced conditions including CD alter the anti-inflammatory properties of these cells [16][17][18]. Remarkably, the altered properties of hASCs persist even when patients with CD are in remission, in all AT depots explored including subcutaneous fat [18].…”

Section: Introductionmentioning

confidence: 99%

“…Of note, some metabolic stress-induced conditions including CD alter the anti-inflammatory properties of these cells [16][17][18]. Remarkably, the altered properties of hASCs persist even when patients with CD are in remission, in all AT depots explored including subcutaneous fat [18]. The constancy of this dysfunctional phenotype might reflect changes at the epigenetic level, which ultimately hamper the resolution of the inflammatory events in the sinus of the affected mesenteric AT.…”

Section: Introductionmentioning

confidence: 99%

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Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

et al. 2020

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Background: Crohn's disease (CD) is characterized by persistent inflammation and ulceration of the small or large bowel, and expansion of mesenteric adipose tissue, termed creeping fat (CF). We previously demonstrated that human adipose-derived stem cells (hASCs) from CF of patients with CD exhibit dysfunctional phenotypes, including a pro-inflammatory profile, high phagocytic capacity, and weak immunosuppressive properties. Importantly, these phenotypes persist in patients in remission and are found in all adipose depots explored including subcutaneous fat. We hypothesized that changes in hASCs are a consequence of epigenetic modifications. Methods: We applied epigenome-wide profiling with a methylation array (Illumina EPIC/850k array) and gene expression analysis to explore the impact of CD on the methylation signature of hASCs isolated from the subcutaneous fat of patients with CD and healthy controls (n = 7 and 5, respectively; cohort I). Differentially methylated positions (p value cutoff < 1 × 10 −4 and ten or more DMPs per gene) and regions (inclusion threshold 0.2, p value cutoff < 1 × 10 −2 and more than 2 DMRs per gene) were identified using dmpfinder and Bumphunter (minfi), respectively. Changes in the expression of differentially methylated genes in hASCs were validated in a second cohort (n = 10/10 inactive and active CD and 10 controls; including patients from cohort I) and also in peripheral blood mononuclear cells (PBMCs) of patients with active/inactive CD and of healthy controls (cohort III; n = 30 independent subjects). Results: We found a distinct DNA methylation landscape in hASCs from patients with CD, leading to changes in the expression of differentially methylated genes involved in immune response, metabolic, cell differentiation, and development processes. Notably, the expression of several of these genes in hASCs and PBMCs such as tumor necrosis factor alpha (TNFA) and PR domain zinc finger protein 16 (PRDM16) were not restored to normal (healthy) levels after disease remission. Conclusions: hASCs of patients with CD exhibit a unique DNA methylation and gene expression profile, but the expression of several genes are only partially restored in patients with inactive CD, both in hASCs and PBMCs. Understanding how CD shapes the functionality of hASCs is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies.

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Section: Immune Systemsupporting

confidence: 93%

Section: Differentially Methylated Positions In Adipose Stem Cells Ismentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

et al. 2020

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“…The impact of donor age on MSC characteristics was demonstrated by Lo Surdo and colleagues, who showed that among MSC cell lines developed from eight donors, the cells from the oldest two donors had the lowest proliferative index and lowest colony‐forming unit percentage at P3. In terms of the patient's disease or condition, pioneering work from the laboratory of Vendrell showed that AD‐MSCs derived from the subcutaneous fat of patients with Crohn's disease exhibited an activated immune response and reduced immunosuppressive capabilities when compared to AD‐MSCs from healthy donors . On the other hand, allogeneic cells are derived from healthy and potentially younger donors, and the risk of rejection of the allogeneic MSCs by patients' immune cells is significantly minimized due to poor HLA Class I expression and absence of Class II expression by MSCs …”

Section: Discussionmentioning

confidence: 99%

Modifiers of mesenchymal stem cell quantity and quality

et al. 2018

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Therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles: A focus on inflammatory bowel disease

Clua‐Ferré,

Suau,

Vañó‐Segarra

et al. 2024

Clinical & Translational Med

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BackgroundMesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC‐EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro‐regenerative, anti‐apoptotic, and antifibrotic properties. Consequently, MSC‐EVs represent a cell‐free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non‐immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage.Main Topics CoveredThis review aims to provide a comprehensive examination of the therapeutic efficacy of MSC‐EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC‐EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC‐EV cargoes. We also discuss available preclinical studies demonstrating that MSC‐EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials.ConclusionsFinally, we highlight the potential of MSC‐EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice.Highlights The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC‐derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose‐derived MSC‐EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC‐EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR‐let‐7a is associated with inhibition of apoptosis, miR‐100 supports cell survival, miR‐125b helps suppress pro‐inflammatory cytokines and miR‐20 promotes anti‐inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC‐EVs reduce intestinal inflammation by suppressing pro‐inflammatory mediators (e.g., TNF‐α, IL‐1β, IL‐6) and increasing anti‐inflammatory factors (e.g., IL‐4, IL‐10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

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Crohn's Disease Disturbs the Immune Properties of Human Adipose-Derived Stem Cells Related to Inflammasome Activation

Cited by 53 publications

References 42 publications

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

Modifiers of mesenchymal stem cell quantity and quality

Therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles: A focus on inflammatory bowel disease

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