Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy,neurosensory impairments,and cognitive deficits,and there is no effective treatment for complications related to hypoxic-ische...Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy,neurosensory impairments,and cognitive deficits,and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy.The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored.However,the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated.In this study,we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function.Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats.Following transplantation of human placental chorionic plate-derived mesenchymal stem cells,interleukin-3 expression was downregulated.To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy,we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA.We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown.Furthermore,interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy.The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy,and this effect was mediated by interleukin-3-dependent neurological function.展开更多
Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis.While mesenchymal stem cell(MSC)therapy holds promise,poor survival and inconsistent paracrine...Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis.While mesenchymal stem cell(MSC)therapy holds promise,poor survival and inconsistent paracrine function limit efficacy.Herein,we present a novel biohybrid strategy that synergistically combines microbe-mimetic preconditioning of MSCs with bacterial cell wall components(peptidoglycan,PGN and lipoteichoic acid,LTA)and their sustained delivery within a gelatin methacryloyl(GelMA)hydrogel(plMSC-GelMA)to overcome these limitations.We demonstrate that dual PGN/LTA priming uniquely activates MSCs via Toll-like receptor 2(TLR2),triggering the PI3K/Akt pathway and profoundly enhancing their pro-angiogenic(e.g.,VEGF)and immunomodulatory(e.g.,IL-10,TGF-β)secretome,promoting endothelial cell function and M2 macrophage polarization in vitro.Encapsulation within biocompatible GelMA hydrogel ensured prolonged viability and localized release of these potent factors.In both acute and diabetic murine wound models,plMSC-GelMA significantly accelerated wound closure,surpassing unprimed MSC-GelMA or GelMA alone.This was driven by enhanced neovascularization(CD31+/α-SMA+)and a shift towards pro-healing M2 mac-rophages.Mechanistic studies confirmed the pivotal role of the TLR2-PI3K/Akt axis,as genetic(siRNA)or pharmacological(LY294002)inhibition abolished the enhanced therapeutic benefits of plMSCs.This study uncovers a microbiota-inspired priming strategy that reprograms MSC paracrine function and establishes a translational biohybrid platform(plMSC-GelMA).By harnessing microbial cues and biomaterial engineering,we offer a promising solution for enhancing stem cell therapy in refractory diabetic wound healing.展开更多
Background:Eccrine sweat gland(SG)plays a crucial role in thermoregulation but exhibits very limited regenerative potential.Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration,r...Background:Eccrine sweat gland(SG)plays a crucial role in thermoregulation but exhibits very limited regenerative potential.Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration,rebuilding niches in vivo is challenging for stem cell therapeutic applications.Hence,we attempted to screen and tune the critical niche-responding genes that dually respond to both biochemical and structural cues,which might be a promising strategy for SG regeneration.Methods:An artificial SG lineage-restricted niche consisting of mouse plantar dermis homogenates(i.e.biochemical cues)and 3D architecture(i.e.structural cues)was built in vitro by using an extrusion-based 3D bioprinting approach.Mouse bone marrow-derived mesenchymal stem cells(MSCs)were then differentiated into the induced SG cells in the artificial SG lineage-restricted niche.To decouple biochemical cues from structural cues,the transcriptional changes aroused by pure biochemical cues,pure structural cues and synergistic effects of both cues were analyzed pairwise,respectively.Notably,only niche-dual-responding genes that are differentially expressed in response to both biochemical and structural cues and participate in switching MSC fates towards SG lineage were screened out.Validations in vitro and in vivo were respectively conducted by inhibiting or activating the candidate niche-dual-responding gene(s)to explore the consequent effects on SG differentiation.Results:Notch4 is one of the niche-dual-responding genes that enhanced MSC stemness and pro-moted SG differentiation in 3D-printed matrix in vitro.Furthermore,inhibiting Notch4 specifically reduced keratin 19-positive epidermal stem cells and keratin 14-positive SG progenitor cells,thus further delaying embryonic SG morphogenesis in vivo.Conclusions:Notch4 not only participates in mouse MSC-induced SG differentiation in vitro but is also implicated in mouse eccrine SG morphogenesis in vivo.展开更多
Colletotrichum gloeosporioides caused anthracnose in various tropical fruit,resulting in substantial agricultural loss.Anthracnose diseases are mainly managed by chemical fungicides,which excessive use has led to resi...Colletotrichum gloeosporioides caused anthracnose in various tropical fruit,resulting in substantial agricultural loss.Anthracnose diseases are mainly managed by chemical fungicides,which excessive use has led to resistant pathogens and concerns about food safety.In this study,magnolol,a plant-derived active compound from Magnolia officinalis,was investigated.In vivo experiments demonstrated that 4 g L-1magnolol significantly retarded the expansion of anthracnose lesions in mango fruit.Significant inhibition of C.gloeosporioides growth was observed at magnolol concentration higher than 20 mg L-1,with MIC and IC50values of 55.98 and 31.0 mg L-1for mycelial growth,345.68 and 82.37 mg L-1for spore germination,respectively.The inhibitory effect was primarily attributed to the disruption of plasma membrane integrity,which led to the leakage of ion,macro-molecules,nucleic acids and proteins.Furthermore,magnolol induced the accumulation of reactive oxygen species(ROS),resulting in oxidative stress that perturb cellular functions and even induce cell death.Therefore,magnolol has potential as a feasible substitute for controlling anthracnose.展开更多
基金supported by the National Natural Science Foundation of China,No.82001604Guizhou Provincial Higher Education Science and Technology Innovation Team,No.[2023]072+1 种基金Guizhou Province Distinguished Young Scientific and Technological Talent Program,No.YQK[2023]040Guizhou Provincial Basic Research Program(Natural Science),No.ZK[2021]-368(all to LXiong),and Zunyi City Innovative Talent Team Training Plan,No.[2022]-2.
摘要Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy,neurosensory impairments,and cognitive deficits,and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy.The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored.However,the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated.In this study,we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function.Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats.Following transplantation of human placental chorionic plate-derived mesenchymal stem cells,interleukin-3 expression was downregulated.To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy,we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA.We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown.Furthermore,interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy.The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy,and this effect was mediated by interleukin-3-dependent neurological function.
基金supported by the National Nature Science Foundation of China(82472166,32471432,82402934,92468303,U24A20374)the Military Medical Research Projects,Guangdong Major Project of Basic and Applied Basic Research(2023B0303000005)+1 种基金Guangdong Provincial Special Support Program for Prominent Talents(2021JC06Y656)the Science Fund for National Defense Distinguished Young Scholars,and Beijing Natural Science Foundation(L234066).
摘要Chronic diabetic wounds remain a major clinical challenge due to impaired angiogenesis and dysregulated immune homeostasis.While mesenchymal stem cell(MSC)therapy holds promise,poor survival and inconsistent paracrine function limit efficacy.Herein,we present a novel biohybrid strategy that synergistically combines microbe-mimetic preconditioning of MSCs with bacterial cell wall components(peptidoglycan,PGN and lipoteichoic acid,LTA)and their sustained delivery within a gelatin methacryloyl(GelMA)hydrogel(plMSC-GelMA)to overcome these limitations.We demonstrate that dual PGN/LTA priming uniquely activates MSCs via Toll-like receptor 2(TLR2),triggering the PI3K/Akt pathway and profoundly enhancing their pro-angiogenic(e.g.,VEGF)and immunomodulatory(e.g.,IL-10,TGF-β)secretome,promoting endothelial cell function and M2 macrophage polarization in vitro.Encapsulation within biocompatible GelMA hydrogel ensured prolonged viability and localized release of these potent factors.In both acute and diabetic murine wound models,plMSC-GelMA significantly accelerated wound closure,surpassing unprimed MSC-GelMA or GelMA alone.This was driven by enhanced neovascularization(CD31+/α-SMA+)and a shift towards pro-healing M2 mac-rophages.Mechanistic studies confirmed the pivotal role of the TLR2-PI3K/Akt axis,as genetic(siRNA)or pharmacological(LY294002)inhibition abolished the enhanced therapeutic benefits of plMSCs.This study uncovers a microbiota-inspired priming strategy that reprograms MSC paracrine function and establishes a translational biohybrid platform(plMSC-GelMA).By harnessing microbial cues and biomaterial engineering,we offer a promising solution for enhancing stem cell therapy in refractory diabetic wound healing.
基金supported by the NationalNature Science Foundation of China(82002056,32000969,92268206)The general funding grants(2020 M673672)+5 种基金the special funding grants(in-station,2022 T150789)the China Postdoctoral Science Foundation,theMilitaryMedical Research Projects(145AKJ260015000X,2022-JCJQ-ZD-096-00)National key research and development program(2022YFA1104604)Key Support Program for Growth Factor Research(SZYZ-TR-03)the Science Fund for National Defense Distinguished Young Scholars(2022-JCJQ-ZQ-016)Youth Independent Innovation Science Fund Project of PLA General Hospital(22QNFC018).
摘要Background:Eccrine sweat gland(SG)plays a crucial role in thermoregulation but exhibits very limited regenerative potential.Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration,rebuilding niches in vivo is challenging for stem cell therapeutic applications.Hence,we attempted to screen and tune the critical niche-responding genes that dually respond to both biochemical and structural cues,which might be a promising strategy for SG regeneration.Methods:An artificial SG lineage-restricted niche consisting of mouse plantar dermis homogenates(i.e.biochemical cues)and 3D architecture(i.e.structural cues)was built in vitro by using an extrusion-based 3D bioprinting approach.Mouse bone marrow-derived mesenchymal stem cells(MSCs)were then differentiated into the induced SG cells in the artificial SG lineage-restricted niche.To decouple biochemical cues from structural cues,the transcriptional changes aroused by pure biochemical cues,pure structural cues and synergistic effects of both cues were analyzed pairwise,respectively.Notably,only niche-dual-responding genes that are differentially expressed in response to both biochemical and structural cues and participate in switching MSC fates towards SG lineage were screened out.Validations in vitro and in vivo were respectively conducted by inhibiting or activating the candidate niche-dual-responding gene(s)to explore the consequent effects on SG differentiation.Results:Notch4 is one of the niche-dual-responding genes that enhanced MSC stemness and pro-moted SG differentiation in 3D-printed matrix in vitro.Furthermore,inhibiting Notch4 specifically reduced keratin 19-positive epidermal stem cells and keratin 14-positive SG progenitor cells,thus further delaying embryonic SG morphogenesis in vivo.Conclusions:Notch4 not only participates in mouse MSC-induced SG differentiation in vitro but is also implicated in mouse eccrine SG morphogenesis in vivo.
摘要Colletotrichum gloeosporioides caused anthracnose in various tropical fruit,resulting in substantial agricultural loss.Anthracnose diseases are mainly managed by chemical fungicides,which excessive use has led to resistant pathogens and concerns about food safety.In this study,magnolol,a plant-derived active compound from Magnolia officinalis,was investigated.In vivo experiments demonstrated that 4 g L-1magnolol significantly retarded the expansion of anthracnose lesions in mango fruit.Significant inhibition of C.gloeosporioides growth was observed at magnolol concentration higher than 20 mg L-1,with MIC and IC50values of 55.98 and 31.0 mg L-1for mycelial growth,345.68 and 82.37 mg L-1for spore germination,respectively.The inhibitory effect was primarily attributed to the disruption of plasma membrane integrity,which led to the leakage of ion,macro-molecules,nucleic acids and proteins.Furthermore,magnolol induced the accumulation of reactive oxygen species(ROS),resulting in oxidative stress that perturb cellular functions and even induce cell death.Therefore,magnolol has potential as a feasible substitute for controlling anthracnose.