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Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Neural Regeneration Research 2024年第6期19卷 1249-1255页

作者： Shuho Gotoh Masahito Kawabori Miki Fujimura Department of Neurosurgery Hokkaido University Graduate School of Medicine

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including antiapoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

关键词： central nervous system disease exosome extracellular vesicle intranasal administration stem cell

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CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of stem cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for stem cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for stem cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

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Allogenic stem cell Transplantation and COVID-19 Antibodies: Mechanistic Insights and Recipient Concerns

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Open Journal of Immunology 2024年第2期14卷 16-32页

作者： Amna Umer Asma Umer Khayam Nasar Khan David Lawrence Greene Umm E. Habiba Sabiha Shamim Pak-American Hospital Pvt. Ltd. Islamabad Pakistan R3 Medical Research LLC Scottsdale USA Bello Bio Labs and Therapeutics (SMC) Pvt. Ltd. Islamabad Pakistan Department of Biochemistry Rawalpindi Medical University Rawalpindi Pakistan Bello Bio LLC Scottsdale USA

Collecting umbilical cord stem cells is widely practiced due to its numerous benefits. Over the past decade, umbilical cord stem cells (UCSCs) have shown effectiveness in treating various conditions, such as bone pathologies, neuropsychiatry disorders, hereditary diseases, and metabolic disorders. However, factors like immunization affect the quantity and quality of cord harvesting. Studies suggest that antibodies from the mother pass through the umbilical cord to protect the infant against infections. Cleaning the umbilical cord before stem cell extraction is crucial to maintain sterility and cell integrity. Vaccinating a female donor, including for COVID-19, typically does not directly affect the stem cells. Although vaccines aim to trigger an immunological response, they generally do not affect the donor’s stem cells.

关键词： Vaccination stem cell Allogeneic COVID Antibodies

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stem cell niche-inspired microcarriers with ADSCs encapsulation for diabetic wound treatment

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Bioactive Materials 2023年第8期26卷 159-168页

作者： Xiangyi Wu Haofang Zhu Junyi Che Ye Xu Qian Tan Yuanjin Zhao Department of Burns and Plastic Surgery Institute of Translational MedicineThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210002China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China

stem cell therapies have made great progress in the treatment of diabetic wounds during recent decades,while their short in vivo residence,alloimmune reactions,undesired behaviors,and dramatic losses of cell functions still hinder the translation of them into clinic.Here,inspired by the natural components of stem cell niches,we presented novel microfluidic hydrogel microcarriers with extracellular matrix(ECM)-like composition and adipose-derived stem cells(ADSCs)encapsulation for diabetic wound healing.As the hydrogel was synthesized by conjugating hyaluronic acid methacryloyl(HAMA)onto the Fibronectin(FN)molecule chain(FN-HAMA),the laden ADSCs in the microcarriers showed improved bioactivities and pro-regenerative capabilities.Based on these features,we have demonstrated that these ADSCs microcarriers exhibited significant promotion of neovascularization,follicular rejuvenation,and collagen deposition in a mouse diabetic wound model.These results indicated that the stem cell niche-inspired FN-HAMA microcarriers with ADSCs encapsulation have great clinical potential for diabetic wound treatment.

关键词： stem cell Bio-inspired Microfluidics Microcarrier Wound healing Hydrogel

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stem cell therapy in retinal diseases

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Neural Regeneration Research 2023年第7期18卷 1478-1485页

作者： Audrey Voisin Amaury Pénaguin Afsaneh Gaillard Nicolas Leveziel Laboratoire de Neurosciences Expérimentales et Cliniques Universitéde PoitiersINSERM 1084PoitiersFrance Department of Ophthalmology CHU PoitiersPoitiersFrance Laboratoires Thea Clermont-FerrandFrance

Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in the field of retinal disorders,there is currently no curative treatment.Several therapeutic approaches such as cell-based replacement and gene therapies are currently in development.In the context of cell-based therapies,different cell sources such as embryonic stem cells,induced pluripotent stem cells,or multipotent stem cells can be used for transplantation.In the vast majority of human clinical trials,retinal pigment epithelial cells and photoreceptors are the cell types considered for replacement cell therapies.In this review,we summarize the progress made in stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.

关键词： age-related macular degeneration cell transplantation clinical trial retinal disease retinal dystrophy stem cell

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Adipose-derived stem cell/FGF19-loaded microfluidic hydrogel microspheres for synergistic restoration of critical ischemic limb

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Bioactive Materials 2023年第9期27卷 394-408页

作者： Ruihan Wang Fangqian Wang Shan Lu Bin Gao Yuanqing Kan Tong Yuan Yisheng Xu Chen Yuan Daqiao Guo Weiguo Fu Xiaohua Yu Yi Si Department of Vascular Surgery Zhongshan Hospital Fudan UniversityShanghai200032PR China Institute of Vascular Surgery Fudan UniversityShanghai200032PR China National Clinical Research Center for Interventional Medicine Shanghai200032PR China Department of Orthopedics The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou310009ZhejiangPR China Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou310000ZhejiangPR China State Key Laboratory of Chemical Engineering East China University of Science and TechnologyShanghai200237China

The efficacy of stem cell therapy is substantially compromised due to low cell survival rate and poor local retention post-delivery. These issues drastically limit the application of stem cells for ischemic limb therapy, which requires effective blood perfusion and skeletal muscle regeneration. Herein, based on microfluidic technology, an integrated stem cell and cytokine co-delivery system designed for functional ischemic limb salvage was constructed by first incorporating the myogenic cytokine, fibroblast growth factor 19 (FGF19), into microspheres composed of methacrylate gelatin (GelMA). Then adipose-derived stem cells (ADSCs) were highly absorbed into the porous structure of the microspheres, overcoming the insufficient loading efficiency and activities by conventional encapsulation strategy. The fabricated ADSCs/FGF19@μsphere system demonstrated a uniform size of about 180 μm and a highly porous structure with pore sizes between 20 and 40 μm. The resultant system allowed high doses of ADSCs to be precisely engrafted in the lesion and to survive, and achieved sustained FGF19 release in the ischemic region to facilitate myoblast recruitment and differentiation and myofibrils growth. Furthermore, the combination of ADSCs and FGF19 exhibited a positive synergistic effect which substantially improved the therapeutic benefit of angiogenesis and myogenesis, both in vitro and in vivo. In summary, a stem cell and cytokine co-delivery system with the properties of easy preparation and minimal invasiveness was designed to ensure highly efficient cell delivery, sustained cytokine release, and ultimately realizes effective treatment of ischemic limb regeneration.

关键词： Microfluidic technology stem cell Cytokine Porous microspheres Ischemic limb salvage

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Techniques for increasing the yield of stem cell-derived exosomes:what factors may be involved?

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Science China(Life Sciences) 2022年第7期65卷 1325-1341页

作者： Zi-Yuan Feng Qing-Yi Zhang Jie Tan Hui-Qi Xie Laboratory of stem cell and Tissue Engineering Orthopedic Research InstituteMed-X Center for MaterialsState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine.Nevertheless,limited yield has restrained full explication of their functions and clinical applications.To address this,various attempts have been made to explore the up-and down-stream manipulations in a bid to increase the production of exosomes.This review has recapitulated factors which may influence the yield of stem cell-derived exosomes,including selection and culture of stem cells,isolation and preservation of the exosomes,and development of artificial exosomes.

关键词： exosome stem cell yield therapy

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Progress and expectation of stem cell therapy for diabetic wound healing

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World Journal of Clinical Cases 2023年第3期11卷 506-513页

作者： Zhen-Han Xu Meng-Hui Ma Yan-Qing Li Li-Lin Li Gui-Hua Liu Reproductive Medicine Center The Sixth Affiliated HospitalSun Yat-Sen UniversityGuangzhou 510610Guangdong ProvinceChina

Impaired wound healing presents great health risks to diabetics.Encouragingly,the current clinical successfully found out meaningful method to repair wound tissue,and stem cell therapy could be an effective method for diabetic wound healing with its ability to accelerate wound closure and avoid amputation.This minireview aims at introducing stem cell therapy for facilitating tissue repair in diabetic wounds,discussing the possible therapeutic mechanism and clinical application status and problems.

关键词： stem cell Diabetic wound Wound healing Immunoregulation

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Clinical efficacy analysis of mesenchymal stem cell therapy in patients with COVID-19:A systematic review

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World Journal of Clinical Cases 2022年第27期10卷 9714-9726页

作者： Jun-Xia Cao Jia You Li-Hua Wu Kai Luo Zheng-Xu Wang Biotherapy Center The Seventh Medical Center of People's Liberation Army General HospitalBeijing 100700China

BACKGROUND Currently,ongoing trials of mesenchymal stem cells(MSC)therapies for coronavirus disease 2019(COVID-19)have been reported.AIM In this study,we investigated whether MSCs have therapeutic efficacy in novel COVID-19 patients.METHODS Search terms included stem cell,MSC,umbilical cord blood,novel coronavirus,severe acute respiratory syndrome coronavirus-2 and COVID-19,applied to Pub Med,the Cochrane Controlled Trials Register,EMBASE and Web of Science.RESULTS A total of 13 eligible clinical trials met our inclusion criteria with a total of 548 patients.The analysis showed no significant decrease in C-reactive protein(CRP)levels after stem cell therapy(P=0.11).A reduction of D-dimer levels was also not observed in patients after stem cell administration(P=0.82).Furthermore,interleukin 6(IL-6)demonstrated no decrease after stem cell therapy(P=0.45).Finally,we investigated the overall survival(OS)rate after stem cell therapy in COVID-19 patients.There was a significant improvement in OS after stem cell therapy;the OS of enrolled patients who received stem cell therapy was 90.3%,whereas that of the control group was 79.8%(P=0.02).CONCLUSION Overall,our analysis suggests that while MSC therapy for COVID-19 patients does not significantly decrease inflammatory markers such as CRP,D-dimer and IL-6,OS is improved.

关键词： stem cell Meta-analysis COVID-19 Mesenchymal stem cells

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Early diagnostic value of liver stiffness measurement in hepatic sinusoidal obstruction syndrome induced by hematopoietic stem cell transplantation

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World Journal of Clinical Cases 2022年第26期10卷 9241-9253页

作者： You-Wen Tan Yi-Chun Shi Department of Hepatology The Third Hospital of Zhenjiang Affiliated Jiangsu UniversityZhenjiang 212003Jiangsu ProvinceChina

Hematopoietic stem cell transplantation(HSCT)-sinusoidal obstruction syndrome(SOS),also known as veno-occlusive disease,is a clinical syndrome characterized by symptoms,such as right upper quadrant pain,jaundice,fluid retention,and hepatomegaly,and is caused by pre-treatment-related hepatotoxicity during the early stages after HSCT.Clinical diagnosis of HSCT-SOS is based on the revised Seattle or Baltimore standards.The revised standard by the European Society for Bone Marrow Transplantation in 2016 has good practicability and can be used in combination with these two standards.Eight studies have shown the value of liver stiffness measurement(LSM)in the early diagnosis of HSCT-SOS.Four studies investigated LSM specificity and sensitivity for the early diagnosis of HSCT-SOS.LSM can distinguish SOS from other post-HSCT complications,enabling a clear differential diagnosis.It has been shown that median LSM of patients with SOS is significantly higher than that of patients with other treatment-related liver complications(e.g.,acute cholecystitis,cholangitis,antifungal drug-related liver injury,liver graft-versus-host disease,isolated liver biochemical changes,and fulminant Epstein Barr virus related hepatitis reactivation).Therefore,the above data confirmed the utility of LSM and strongly suggested that LSM improves the positive predictive value of the SOS diagnostic clinical score after allogeneic HSCT.Early diagnosis of SOS is beneficial in preventing severe HSCT complications.

关键词： Hematopoietic stem cell transplantation Sinusoidal obstruction syndrome Liver stiffness measurement stem cell

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