干细胞治疗结肠炎/靶向治疗结肠炎

Intestinal stem cells (ISCs) engage in proliferation to maintain a stable stem cell population and differentiate into functional epithelial subpopulations. This intricate process is upheld by various signals derived from the host and gut microbiota, establishing an ISC niche. However, during inflammatory bowel disease (IBD), this signaling niche undergoes dramatic changes, leading to impaired ISC and hindered restoration of the damaged intestinal epithelial barrier. This study introduces intestinal inflammatory microenvironment-responsive microsphere vehicles designed to remodel the ISC niche, offering an approach to treat IBD. Using an advanced emulsion technique, these microsphere vehicles specifically target colonic inflammation sites, delivering a responsive release of MXene and l-arginine. This delivery system is formulated to modulate intestinal flora and immune responses effectively. l-arginine is converted into nitric oxide to regulate the gut microbiome, while MXene serves as a nanoimmunomodulator to stabilize immune homeostasis. Our findings demonstrate that the anti-inflammatory properties of the microspheres are key to promoting epithelial repair and remodeling of the ISC niche. This study highlights the role of antioxidant microspheres as anti-inflammatory agents that indirectly support ISC function and gut regeneration.

Rationale: Inflammatory bowel disease (IBD) is a relapsing and idiopathic disorder. The low therapeutic efficacy of IBD urgently prompts us to seek new treatment methods. Methods and Results: In this study, we report an adipose-derived mesenchymal stem cell (AT-MSC)-based treatment strategy in which AT-MSCs specifically deliver BMP inhibitor Grem1 and anti-inflammatory factor IL-10 to inflammatory colon tissues in SETD2 deficient dextran sulfate sodium (DSS)-induced colitis mouse models. Targeted delivery of Grem1 reduced colitis by promoting intestinal stem cell regeneration and enhancing mucosal regenerative capacity. Furthermore, targeted delivery of IL-10 reduced colitis by reducing inflammatory cytokines. Conclusion: Our AT-MSCs based therapeutic strategy effectively mitigated IBD. This study has deepened our understanding of IBD therapy and provided a theoretical foundation for its clinical treatment.

Summary Background Inflammatory bowel disease (IBD) remains a therapeutic challenge due to its chronic relapsing nature and limited long-term remission strategies. Here, we propose a therapy using stem cells from human exfoliated deciduous teeth (SHEDs). Methods We evaluated SHEDs in murine colitis models (DSS/TNBS) and human IBD tissues. Single-cell RNA sequencing (scRNA-seq) and organoid cocultures were used to characterise SHED differentiation and therapeutic mechanisms. Findings SHEDs migrate to inflamed intestines, differentiate into TGM2+TFPI2+ quiescent fibroblast-like synovial cells (QFLSs) via a β-catenin-independent Wnt/JNK pathway, and significantly ameliorate colitis in preclinical models. Mechanistically, QFLSs exhibit dual therapeutic actions: (1) IL-6 secretion promoted Paneth cell proliferation to restore crypt homoeostasis; and (2) LIF-driven expansion of immunosuppressive Treg cells reshaped the inflammatory microenvironment. Crucially, we validated the presence of QFLSs in human IBD tissues, where their abundance correlated with reduced disease severity and improved prognosis. Interpretation Our study identified SHED-derived QFLSs as multifunctional mediators that concurrently addressed epithelial damage and immune dysregulation in IBD. This cell-based strategy overcame spatial limitations of traditional therapies by leveraging endogenous repair pathways, offering a translatable blueprint for chronic inflammatory diseases. Funding Supported by 10.13039/501100004826Beijing Natural Science Foundation (7242034, 7242092, L232077), 10.13039/100014717National Natural Science Foundation of China (81870393, 81970500, 82473154, 81970500, and 82203559), and Jiangsu Province Basic Research Special Fund (BK20240117).

Mesenchymal stromal cells (MSCs) are considered a promising cell‐based therapy for inflammatory bowel disease (IBD), due to their potent immunomodulatory properties and robust regenerative potential. However, their therapeutic efficacy against IBD is hindered by poor homing capacity and excessive leukocyte infiltration at inflamed colonic sites. In this study, MSCs with a Y‐shaped bispecific antibody (YMV) assembled via DNA nanotechnology, which integrates anti‐vascular cell adhesion molecule‐1 (anti‐VCAM‐1) and anti‐mucosal addressing cell adhesion molecules‐1 (anti‐MAdCAM‐1) antibodies are engineered, to enhance targeted delivery and inhibit leukocyte recruitment. YMV‐modified MSCs show an approximately threefold enhancement in adhesion efficiency compared with native MSCs. Notably, they effectively compete for MAdCAM‐1 binding sites and significantly suppress leukocyte adhesion. In a mouse model of IBD, YMV‐MSCs demonstrate enhanced homing to the colon, promote mucosal repair, reduce leukocyte infiltration, and attenuate local inflammation. This DNA‐mediated bispecific antibody modification strategy improves MSCs targeting and exerts anti‐inflammatory effects by blocking leukocyte recruitment, offering a promising platform for MSC‐based therapy.

Therapeutic strategies that can target multilevel immunoregulatory pathways in inflammatory bowel disease (IBD) and efficiently target the site of inflammation are expected to greatly enhance the therapeutic efficacy. Here, we have developed a DNA nanorobot-armed bidirectional resistant mesenchymal stem cell (MSC) for IBD treatment, which blocks lymphocyte infiltration at the site of inflammation by bidirectional inhibition of integrin-ligand inter-recognition via resistant aptamer-hands. And this strategy can induce MSC homing for immunomodulation and tissue repair. Herein, in this nanorobot, tetrahedral DNA (TDN) serves as a communication bridge, Integrin α4 and VCAM 1 aptamers are equipped to two vertices of TDN, and the other two cholesterol vertices of TDN are used for immobilization on MSC. In murine colitis models, tail vein-injected resistant MSC preferentially and rapidly accumulated in the inflamed colon and have been more effective in reducing colonic inflammation than pure MSC or aptamers bidirectional inhibitors. The therapeutic strategy proposed in this work has minimal systemic side effects and holds therapeutic promise for a subgroup of IBD patients who do not respond to single anti-inflammatory therapies.

Inflammatory bowel disease (IBD), including Crohn's disease (CD; Th1/Th17-driven) and ulcerative colitis (Th2-skewed), lacks therapies correcting T-cell imbalance. Current cytokine-focused treatments remain ineffective, while mesenchymal stromal cells (MSCs) therapies are hindered by inherent heterogeneity and challenges related to cell viability maintenance, batch-to-batch consistency, and standardization. This study aimed to (Kaplan, 2015 (1)) identify MSCs subtypes targeting CD pathology, Sebastian and Siegmund (2024) (2) create MSCs-mimicking nanoparticles, and (Li et al., 2016 (3)) propose a "deconstructed cell therapy" framework. Using colon datasets and CD blood samples, Th1/Th17-macrophage dysregulation was mapped. Transcriptomic screening of eight MSCs sources identified dental pulp-derived TLR5high-MSCs as superior Th1/Th17 inhibitors compared to umbilical cord TLR5low-MSCs. In colitis models, TLR5high-MSCs intercepted gut flagellin (Fla), blocking macrophage TLR5/NF-κB to restore T-cell balance. Decellularized MSCs membranes were engineered into nanovesicles (TLR5high-CMNP), which showed 3.7-fold higher Fla. affinity than antibodies and suppressed Th1/Th17 activity in vitro. In murine colitis, TLR5high-CMNP achieved comparable efficacy to MSCs (e.g., 68.9 % reduction in MPO scores), while avoiding challenges associated with live-cell administration - such as embolism occurrence (0 % vs. 24 % in MSCs), need for viability maintenance, and potential variability in TLR5 expression. Bioinformatic analysis confirmed TLR5 as pivotal for MSCs specificity, enabling tailored nanoparticle design. This study highlights TLR5high-CMNP as a safer, cell-free MSCs alternative and introduces a paradigm prioritizing precise immune checkpoint targeting (e.g., Fla./TLR5) over broad cytokine suppression, resolving IBD therapeutic ambiguity through scalable biomimetic nanomaterials.

… Inflammatory bowel disease (IBD) is an incurable condition driven by chronic inflammatory dysregulation. Human mesenchymal stem cells (hMSCs) offer therapeutic promise, but …

Current therapies for inflammatory bowel disease (IBD) often fail to achieve complete remission and are associated with systemic toxicity owing to their broad immunosuppressive effects. To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton’s jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3⁺ regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.

Rationale: Mesenchymal stem cells (MSCs) possess potent immunomodulatory capability, but occasionally, clinical application of MSCs is hindered by compromised cell functionality and insufficient therapeutic efficacy. Methods: Here, well-established mouse models of dextran sulfate sodium (DSS)-induced colitis and streptozotocin (STZ)-induced type 1 diabetes (T1D) were used to evaluate therapeutic immunomodulatory effects of human umbilical cord-derived MSCs. MSCs were examined at the fifth (P5) and the fifteenth (P15) passages, and three-dimensional (3D) culture was conducted by Matrigel incorporation. A series of biochemical, histopathological and cellular assays were performed to investigate the MSC function and therapeutic performance, and immunoregulation was evaluated by in vitro co-culture with T cells and in vivo analyses of T-cell infiltration into target tissues. RNA sequencing (RNA-seq) analysis followed by immunofluorescence staining, gene expression analyses and chemical regulation were used to investigate the molecular targets. Results: MSCs lose therapeutic immunomodulatory effects after extensive expansion to P15 when cell senescence occurs. Intriguingly, 3D preconditioning of MSCs in Matrigel promotes diminished immunoregulatory capability despite extensive passages, which benefits function of P15-MSCs to modulate T-cell subsets in co-culture, suppress infiltration of pro-inflammatory T cells in the colon and pancreas tissues after infusion, ameliorate systemic inflammation, and alleviate colitis and T1D in mice. Mechanistically, 3D culture provokes transcriptomic reprogramming of MSCs toward a Yes-associated protein 1 (YAP1)-marked, Hippo signaling pathway-upregulated state with promoted release of the anti-inflammatory cytokine, transforming growth factor-beta1 (TGF-β1). Moreover, chemical regulation of YAP1 by clinically relevant drugs, verteporfin (VP) and prostaglandin E2 (PGE2), affects TGF-β1 expression and the immunomodulatory capability of MSCs during dimensional culture. Conclusions: Taken together, these findings unravel YAP1-based dimensional and chemical coordination of expanded MSC immunoregulation, which will shed light on precisely controlled translational application.