YAP1 mediates the dimensional and chemical coordination of immunoregulation and therapy in extensively passaged mesenchymal stem cells

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1930 - 1948

Published: Jan. 6, 2025

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

Language: Английский

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Exosome Source Matters: A Comprehensive Review from the Perspective of Diverse Cellular Origins

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(2), P. 147 - 147

Published: Jan. 22, 2025

Exosomes have emerged as promising therapeutic agents in regenerative medicine. This review introduces a novel cell type-oriented perspective to systematically analyze exosomal properties therapies. To our knowledge, this is the first comprehensively compare exosomes based on cellular source type, offering unprecedented insights into selecting optimal exosome producers for targeted applications. Factors beyond origin influencing efficacy, such donor sites and collection methods, are also explored here. By synthesizing key advances, we propose research directions end. We aim accelerate development of more effective exosome-based therapies highlight underexplored rapidly evolving field.

Language: Английский

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Immune modulatory stem cells represent a significant component of the immune system

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 3, 2025

Stem cells are an important compartment supporting tissues with differentiating and responding to regeneration demand[1–4]. There interesting evidences that subpopulations of stem migrate developing organs during embryogenesis, but do not directly contribute development[5–10]. They persist provide support as the adult organism. If more would have proliferative differentiation potential cells, it be good for regeneration. However, should balanced risks mutations oncogenesis. A self-maintaining, highly cell need fewer changes become a cancer cell. The quiescence high could solution place them evolutionarily further away from cells[11]. Slow dividing also lower mutation associated number divisions[11,12]. Lower mutational is resistance oncogenesis, well neoantigens consequently autoimmunity[13]. These reasons important, in context long-living strategies, there benefits keeping quiescent short-term? coupled their metabolic processes, enables survive severely damaged tissues, thereby facilitating regeneration[14,15]. Given role regeneration, increase expected enhance regenerative potential. stroma maintained at proportion 10-5-10-4[16–21]. maintain this relatively low level. An note increased suggests divisions each, way significantly reducing chance random cooperation oncogenic single cell, lowering risk[11]. explanation matter energy consumption efficiency. tenfold change results mere 0.1% alteration total value. More firm derived immunomodulatory properties cells. Pronounced diverse immune modulation mesenchymal cells(MSCs)earlier led identification agents system[22,23]. demonstrated later rejection transplantations ceased idea[24,25]. Recently, privileges(IPs)of including MSCs, been demonstrated[20,26–28]. It was previously suggested IPs state relate inflammation regulation[26,29]. molecular mechanisms exerted by qualifying modulatory cells(IMSCs)[30]. That way, IMSCs demonstrating active participation regulation capability IPs. I propose generalized model functionally links newly other attributes IMSCs. functional significance particular evolutionary importance respect systems[29]. reports indicate MSCs only evade cytotoxic action[31], actively attract can activate or reprogram depending on context[32–36]. Immune employed solid organ transplantation utilized treatment autoimmune pathology[32–35]. This gives ground mark baring suppression activation subsequent induction program inflammatory program[34,37]. shown express range immunosuppressing molecules, PGE2,TGF‐β,HLA-G5,IL‐10,HGF,galectins,CD73 CD39,PD-L1,HLA-G1 other[30,34,37,38]. Immunomodulatory capabilities pronounced than differentiated cells[39,40]. challenging determine where functions lost progeny, particularly light dedifferentiation[41,42]. existing mutual integration systems highlights integration, additional mechanism may potentially act break point. underscores necessity coordination involved integration. construction comprehensive hindered vast elements incomplete knowledge about connections. Therefore, model(Figure1).As upon activation[32,34,37], they remain inactive. Otherwise, compromise protection tissue invading pathogens. higher concentration suppression, so reasoning limited numbers(Figure1). In manner, serve activating special agent periphery, suppressing destructive actions overactive system. offers rationale maintenance IMSC numbers. traumas infections life cancer, possibly stronger selective pressure long-term living strategies stay actual even short-term strategies.In event infection, resident signal among activation[35,36,43]. induces signals slower rate initial proinflammatory reaction. allows necessary time acute reaction occur(Figure1). Upon activation, sites damage[17,19,44,45], exert immunosuppressive effects. Over time, response stimulates system, inducing its anti-inflammatory functions. As result, initially inflamed area becomes polarized toward subtype.Immune exploited pathogens[43,46,47]. system responsible protecting against oncogenesis[48], emphasizes IPs[46,49,50]. presented complex enigmatic regulation, which serves natural barrier hijacking. Furthermore, regulatory must robust. provided strong connection function small subpopulation pathogens target immunosuppression, infection evolve order fit specific conditions niche. physiology exchange enable survival infection[51,52]. fitness pathogen subgroup render ineffective exerting selection such fitness(Figure1). isolation small, provides robust form infection. coevolution represents dynamic interdependent relationship[46]. lack absolute infected[43,47]. When infected, suppress direct antiviral action through apoptosis[53,54].This seeding embryogenesis[5]. between embryonic contexts attributed heightened risk invasions lifespan. pivotal function, divergence status preceding following labor adaptation.The differences distinguish otherwise lethal majority cells[15,51]. tissues. model, possess IPs, implies restoration areas afflicted excessive inflammation. different paucity migration contaminated diminished.The proposes perspective IMSCs, MSC, identified various human body[55]. MUSE VSELs modulation, organs[28,56,57]. similarities immune-privileged hair follicle muscle hematopoietic require definition[26,27]. proposed does align organizational structure all examples organizations significant adjustments[58]. esophageal epithelium illustrative example wherein 65% engaged proliferation, self-maintaince, repair-related fulfilling functions[59]. Lgr5+ colon intestine demonstrate sustained activity throughout lifespan[60–62]. cycling illustrate solutions tissue-specific addition quiescence, protect mutations[63]. Proliferating exhibit same cells[26]. disparate patterns regulation. liver damage mediated hepatocytes biliary epithelial homeostasis, yet undergo event[64]. parenchymal primary contributors cellular restoration[65,66]. Wound activates upregulates dedifferentiation[67]. Dedifferentiation regulate pool[68]. subject negative feedback, whereby inhibit dedifferentiation reduce surrounding cells[69,70]. Further studies required elucidate experimental study distinction quiescent, experiments nuances across tissues.The logical difficulties expanding used clinic pathological immunotoxicity[28,32,34,71–75]. extended attribute state[49,50]. non-cancerous conceptualizing cancerous region activated[67,76,77]. stimulation non-cancer therapy damages tissue, stimulating regeneration[78,79]. recognized scientific community[32,34,71,73]. principal objective article designate component acknowledged part peripheral control autoimmunity, potential.The establishes link modulation. analysis, eschewing detailed examination underlying mechanisms. simultaneously, forming network. robustness beyond this. Additional restrictions imposed overall offer compelling observed values. To present perspective, data necessarily context-specific theory. Nevertheless, deep foundation model. realized mechanism. Alternatively, adjusted independent shifts, advantages generations. attributes. presentation account process analysis involved. these issues warrant investigation.

Language: Английский

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Influencing factors and mechanism of hepatocyte regeneration

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 30, 2025

As a research hotspot in the field of regenerative medicine, hepatocyte regeneration has great potential treatment liver diseases. This paper comprehensively summarizes diverse sources and its complex influencing factors, deeply discusses typical mechanism. According to existing research, we observed that Wnt signaling pathway Notch can play synergistic role process regeneration. So further analyzed crosstalk between signal cross mechanism with TGF-β, YAP/TAZ during Despite remarkable progress study at cellular molecular levels, comprehensive understanding fine regulation factors interaction mechanisms still needs be deepened. aims systematically analyze classical by integrating multi-group data advanced bioinformatics methods, so as provide feasible ideas for diseases lay solid theoretical foundation future development medicine. It is believed focusing on rational innovative means such inducing gene tendentiousness expression anti-aging therapy, in-depth analysis interactive network are expected open up new road more effective strategies

Language: Английский

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Organoid‐tissue extracellular vesicles

Deleted Journal, Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

Abstract Extracellular vesicles (EVs) are lipid bilayer structures secreted by cells that act as intercellular messengers. Tissue‐derived EVs (TEVs), harvested from the tissue interstitium, directly reflect actual physiological or pathological state of microenvironment. However, difficulty in acquisition severely limits development TEVs. In contrast, organoids 3D cell clusters cultured stem cells, which have spatial and functions highly similar to source tissues. Although organoid‐derived (OEVs), isolated culture supernatants, can complex cellular interactions, they cannot microenvironment like Building on foundation TEVs OEVs, we introduce innovative concept organoid‐tissue (OTEVs), where residing organoid interstitium. Acting a communication bridge between OEVs TEVs, OTEVs accurately represent true They overcome challenges associated with limited availability inability We believe will synergize enhance understanding pathogenesis diseases, well improve their diagnosis treatment.

Language: Английский

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Hepatocyte‐derived extracellular vesicles regulate liver regeneration through a negative feedback mechanism

Journal of Extracellular Biology, Journal Year: 2024, Volume and Issue: 3(11)

Published: Nov. 1, 2024

Abstract While significant progress has been made in understanding various aspects of liver regeneration, the molecular mechanisms responsible for initiation and termination cell proliferation following massive tissue loss or injury remain unknown. As it was previously shown, mass affects putative hepatocyte‐specific mitogenic inhibitors blood. Although presence these regulating precise regeneration described numerous publications, they have never identified. Extracellular vesicles (EVs) are nano‐sized, membrane‐limited structures secreted by cells into extracellular space. Their proposed role is stable intercellular carriers proteins RNAs, predominantly micro‐RNA, from to recipient cells. Upon uptake cells, EVs can significantly modulate their biological functions. In present study, using vivo vitro models, we demonstrate that hepatocyte regulated hepatocytes bloodstream. This regulation occurs through a negative feedback mechanism, which explains after damage. We also an essential component this mechanism RNA carried hepatocyte‐derived EVs. Our findings open up new unexplored area biology regarding involved injury. Further study will great influence on development approaches transplantation, pathologies, hepatic tumors.

Language: Английский

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Immune modulating stem cells represent a significant component of the immune system.

Published: Dec. 9, 2024

Stem cells represent a vital component of the body's natural repair mechanisms, providing support for tissues with differentiating and responding to regenerative requests in damaged areas. Mesenchymal stem are additionally known their immunomodulatory properties. The properties these used clinical practice treatment immune-associated dysregulations. derivatives applied organ hematopoietic cell transplantation procedures autoimmune disorders other conditions. Recently immune privileges them few were demonstrated. Existence was reasoned by cross action between processes regeneration inflammation as part peripheral control autoimmunity. A new fundamental feature requires integration into general understanding evolution regulation system. I suggest functional model which links attributes cells, including quiescence, response request, modulation, maintenance homeostatic differences, well low percentage tissues. that modulating (IMSCs) should be recognized relevant

Language: Английский

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