|
1
|
Sharma Y, Mohanty S. Targeted knockdown of MSC-sEVs biogenesis regulator proteins to elucidate the mechanisms of their production: a step towards translational applications. Cytotherapy 2025:S1465-3249(25)00061-1. [PMID: 39985543 DOI: 10.1016/j.jcyt.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 02/24/2025]
Abstract
In the intricate landscape of cellular communication, small extracellular vesicles (sEVs) originating from endosomes play crucial roles as mediators and have garnered significant attention in theranostics. Our understanding of sEV biogenesis largely stems from studies on cancer cells, which are vital for diagnostics. However, in therapeutics, where mesenchymal stromal cell (MSC)-derived sEVs are emerging as investigational new drugs, their biogenesis pathways remain largely unexplored. This article explores the parallel narratives of sEV biogenesis in cancer cells and stem cells, specifically using HeLa cells and MSCs as model cell lines. This study investigated the roles of key proteins-hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), signal-transducing adaptor molecule (STAM), tumor susceptibility gene 101 (TSG101), and ALG-2-interacting protein X (ALIX)-as identified in HeLa cells, in the context of MSC-sEV biogenesis. While these proteins show similarities across cell types, a discernible difference arises in their primary functions in regulating sEV biogenesis. The critical role of ALIX in MSC-sEV biogenesis, in particular, underscores its potential as a target for modulating sEVs' yield in regenerative therapies. Through this comparative analysis, we identified shared molecular signatures, offering insights to guide therapeutic interventions and unlock the regenerative potential of stem cells.
Collapse
Affiliation(s)
- Yashvi Sharma
- Stem Cell Facility-DBT Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility-DBT Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi, India.
| |
Collapse
|
|
2
|
Xu L, Ji J, Wang L, Pan J, Xiao M, Zhang C, Gan Y, Xie G, Tan M, Wang X, Wen C, Fan Y, Chin YE. LIF Promotes Sec15b-Mediated STAT3 Exosome Secretion to Maintain Stem Cell Pluripotency in Mouse Embryonic Development. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2407971. [PMID: 39475099 DOI: 10.1002/advs.202407971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 09/22/2024] [Indexed: 12/28/2024]
Abstract
LIF maintains self-renewal growth in mouse embryonic stem cells (mESC) by activating STAT3, which translocates into nucleus for pluripotent gene induction. However, the ERK signaling pathway activated by LIF at large counteract with pluripotent gene induction during self-renewal growth. Here, it is reported that in mESC STAT3 undergoes multivesicular endosomes (MVEs) translocation and subsequent secretion, LIF-activated STAT3 is acetylated on K177/180 and phosphorylated on Y293 residues within the N-terminal coiled-coil domain, which is responsible for the interaction between STAT3 and Secl5b, an exocyst complex component 6B (EXOC6B). STAT3 translocation into MVEs resulted in the downregulation of T202/Y204-ERK1/2 phosphorylation and up-regulation of S9-GSK3β phosphorylation for maintaining mESC self-renewal growth. STAT3 with K177R/K180R or Y293F substitution fails to execute MVEs translocation and Secl5b-dependent secretion. Mice expressing K177RK180R substitution (STAT3mut/mut) are partially embryonic lethal. In STAT3mut/mut embryos, gene expressions related to hematological system function changed significantly and those living ones carry a series of abnormalities in the hematopoietic system. Furthermore, mice with Secl5b knockout exhibit embryonic lethality. Thus, Secl5b mediated STAT3 MVEs translocation regulates the balance of ERK and GSK3β signaling pathways and maintain mESC self-renewal growth, which is involved in regulating the stability of hematopoietic system.
Collapse
Affiliation(s)
- Li Xu
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Jinjun Ji
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Lingbo Wang
- Clinical Medicine Research Institute, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310014, China
- Group of Epigenetic Reprogramming, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jieli Pan
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Mingzhe Xiao
- Clinical Medicine Research Institute, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310014, China
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Chenxi Zhang
- Clinical Medicine Research Institute, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310014, China
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yihong Gan
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Guanqun Xie
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Mingdian Tan
- Clinical Medicine Research Institute, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310014, China
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xinchang Wang
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China
| | - Chengping Wen
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
| | - Yongsheng Fan
- College of Basic Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310051, China
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China
| | - Y Eugene Chin
- Clinical Medicine Research Institute, Zhejiang Provincial People's Hospital, Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310014, China
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| |
Collapse
|
|
3
|
Matos BMD, Stimamiglio MA, Correa A, Robert AW. Human pluripotent stem cell-derived extracellular vesicles: From now to the future. World J Stem Cells 2023; 15:453-465. [PMID: 37342215 PMCID: PMC10277970 DOI: 10.4252/wjsc.v15.i5.453] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/14/2023] [Accepted: 04/13/2023] [Indexed: 05/26/2023] Open
Abstract
Extracellular vesicles (EVs) are nanometric particles that enclose cell-derived bioactive molecules in a lipid bilayer and serve as intercellular communication tools. Accordingly, in various biological contexts, EVs are reported to engage in immune modulation, senescence, and cell proliferation and differentiation. Therefore, EVs could be key elements for potential off-the-shelf cell-free therapy. Little has been studied regarding EVs derived from human pluripotent stem cells (hPSC-EVs), even though hPSCs offer good opportunities for induction of tissue regeneration and unlimited proliferative ability. In this review article, we provide an overview of studies using hPSC-EVs, focusing on identifying the conditions in which the cells are cultivated for the isolation of EVs, how they are characterized, and applications already demonstrated. The topics reported in this article highlight the incipient status of the studies in the field and the significance of hPSC-EVs’ prospective applications as PSC-derived cell-free therapy products.
Collapse
Affiliation(s)
- Bruno Moises de Matos
- Stem Cells Basic Biology Laboratory, Carlos Chagas Institute, Curitiba 81350010, Paraná, Brazil
| | | | - Alejandro Correa
- Stem Cells Basic Biology Laboratory, Carlos Chagas Institute, Curitiba 81350010, Paraná, Brazil
| | - Anny Waloski Robert
- Stem Cells Basic Biology Laboratory, Carlos Chagas Institute, Curitiba 81350010, Paraná, Brazil
| |
Collapse
|
|
4
|
Aydin S, Pham DT, Zhang T, Keele GR, Skelly DA, Paulo JA, Pankratz M, Choi T, Gygi SP, Reinholdt LG, Baker CL, Churchill GA, Munger SC. Genetic dissection of the pluripotent proteome through multi-omics data integration. CELL GENOMICS 2023; 3:100283. [PMID: 37082146 PMCID: PMC10112288 DOI: 10.1016/j.xgen.2023.100283] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 09/12/2022] [Accepted: 02/27/2023] [Indexed: 04/22/2023]
Abstract
Genetic background drives phenotypic variability in pluripotent stem cells (PSCs). Most studies to date have used transcript abundance as the primary molecular readout of cell state in PSCs. We performed a comprehensive proteogenomics analysis of 190 genetically diverse mouse embryonic stem cell (mESC) lines. The quantitative proteome is highly variable across lines, and we identified pluripotency-associated pathways that were differentially activated in the proteomics data that were not evident in transcriptome data from the same lines. Integration of protein abundance to transcript levels and chromatin accessibility revealed broad co-variation across molecular layers as well as shared and unique drivers of quantitative variation in pluripotency-associated pathways. Quantitative trait locus (QTL) mapping localized the drivers of these multi-omic signatures to genomic hotspots. This study reveals post-transcriptional mechanisms and genetic interactions that underlie quantitative variability in the pluripotent proteome and provides a regulatory map for mESCs that can provide a basis for future mechanistic studies.
Collapse
Affiliation(s)
- Selcan Aydin
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Duy T. Pham
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Tian Zhang
- Harvard Medical School, Boston, MA 02115, USA
| | | | | | | | | | - Ted Choi
- Predictive Biology, Inc., Carlsbad, CA 92010, USA
| | | | - Laura G. Reinholdt
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Christopher L. Baker
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Gary A. Churchill
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Steven C. Munger
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| |
Collapse
|
|
5
|
Extracellular vesicles throughout development: A potential roadmap for emerging glioblastoma therapies. Semin Cell Dev Biol 2023; 133:32-41. [PMID: 35697594 DOI: 10.1016/j.semcdb.2022.05.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.
Collapse
|
|
6
|
Abstract
The Hsp70/Hsp90 organising protein (Hop, also known as stress-inducible protein 1/STI1/STIP1) has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins, although recent evidence suggests that eukaryotic Hop is regulatory within chaperone complexes rather than essential. Consequently, Hop is implicated in many key signalling pathways, including aberrant pathways leading to cancer. Hop is also secreted, and it is now well established that Hop interacts with the prion protein, PrPC, to mediate multiple signalling events. The intracellular and extracellular forms of Hop most likely represent two different isoforms, although the molecular determinants of these divergent functions are yet to be identified. There is also a growing body of research that reports the involvement of Hop in cellular activities that appear independent of either chaperones or PrPC. While the various cellular functions of Hop have been described, its biological function remains elusive. However, recent knockout studies in mammals suggest that Hop has an important role in embryonic development. This review provides a critical overview of the latest molecular, cellular and biological research on Hop, critically evaluating its function in healthy systems and how this function is adapted in diseased states.
Collapse
|
|
7
|
Jin S, Lv Z, Kang L, Wang J, Tan C, Shen L, Wang L, Liu J. Next generation of neurological therapeutics: Native and bioengineered extracellular vesicles derived from stem cells. Asian J Pharm Sci 2022; 17:779-797. [PMID: 36600903 PMCID: PMC9800941 DOI: 10.1016/j.ajps.2022.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/20/2022] [Accepted: 10/10/2022] [Indexed: 11/19/2022] Open
Abstract
Extracellular vesicles (EVs)-based cell-free therapy, particularly stem cell-derived extracellular vesicles (SC-EVs), offers new insights into treating a series of neurological disorders and becomes a promising candidate for alternative stem cell regenerative therapy. Currently, SC-EVs are considered direct therapeutic agents by themselves and/or dynamic delivery systems as they have a similar regenerative capacity of stem cells to promote neurogenesis and can easily load many functional small molecules to recipient cells in the central nervous system. Meanwhile, as non-living entities, SC-EVs avoid the uncontrollability and manufacturability limitations of live stem cell products in vivo (e.g., low survival rate, immune response, and tumorigenicity) and in vitro (e.g., restricted sources, complex preparation processes, poor quality control, low storage, shipping instability, and ethical controversy) by strict quality control system. Moreover, SC-EVs can be engineered or designed to enhance further overall yield, increase bioactivity, improve targeting, and extend their half-life. Here, this review provides an overview on the biological properties of SC-EVs, and the current progress in the strategies of native or bioengineered SC-EVs for nerve injury repairing is presented. Then we further summarize the challenges of recent research and perspectives for successful clinical application to advance SC-EVs from bench to bedside in neurological diseases.
Collapse
Affiliation(s)
- Shilin Jin
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Zhongyue Lv
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Lin Kang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Jiayi Wang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Chengcheng Tan
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Liming Shen
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Liang Wang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Engineering Research Center for Genetic Variation Detection of Infectious Pathogenic Microorganisms, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian 116085, China
| |
Collapse
|
|
8
|
Iglesia RP, Prado MB, Alves RN, Escobar MIM, Fernandes CFDL, Fortes ACDS, Souza MCDS, Boccacino JM, Cangiano G, Soares SR, de Araújo JPA, Tiek DM, Goenka A, Song X, Keady JR, Hu B, Cheng SY, Lopes MH. Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression. Front Cell Dev Biol 2022; 10:907423. [PMID: 35784465 PMCID: PMC9242006 DOI: 10.3389/fcell.2022.907423] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/26/2022] [Indexed: 11/28/2022] Open
Abstract
Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.
Collapse
Affiliation(s)
- Rebeca Piatniczka Iglesia
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil,The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Mariana Brandão Prado
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Nunes Alves
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Isabel Melo Escobar
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Camila Felix de Lima Fernandes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ailine Cibele dos Santos Fortes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Clara da Silva Souza
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jacqueline Marcia Boccacino
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Giovanni Cangiano
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Samuel Ribeiro Soares
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - João Pedro Alves de Araújo
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Deanna Marie Tiek
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Anshika Goenka
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Xiao Song
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Jack Ryan Keady
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Bo Hu
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Shi Yuan Cheng
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Marilene Hohmuth Lopes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil,*Correspondence: Marilene Hohmuth Lopes,
| |
Collapse
|
|
9
|
Hounjet J, Vooijs M. The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation. Biomolecules 2021; 11:biom11091369. [PMID: 34572582 PMCID: PMC8466058 DOI: 10.3390/biom11091369] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.
Collapse
|
|
10
|
Thakur A, Ke X, Chen YW, Motallebnejad P, Zhang K, Lian Q, Chen HJ. The mini player with diverse functions: extracellular vesicles in cell biology, disease, and therapeutics. Protein Cell 2021; 13:631-654. [PMID: 34374936 PMCID: PMC9233731 DOI: 10.1007/s13238-021-00863-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/08/2021] [Indexed: 12/31/2022] Open
Abstract
Extracellular vesicles (EVs) are tiny biological nanovesicles ranging from approximately 30-1000 nm in diameter that are released into the extracellular matrix of most cell types and in biofluids. The classification of EVs includes exosomes, microvesicles, and apoptotic bodies, dependent on various factors such as size, markers, and biogenesis pathways. The transition of EV relevance from that of being assumed as a trash bag to be a key player in critical physiological and pathological conditions has been revolutionary in many ways. EVs have been recently revealed to play a crucial role in stem cell biology and cancer progression via intercellular communication, contributing to organ development and the progression of cancer. This review focuses on the significant research progress made so far in the role of the crosstalk between EVs and stem cells and their niche, and cellular communication among different germ layers in developmental biology. In addition, it discusses the role of EVs in cancer progression and their application as therapeutic agents or drug delivery vehicles. All such discoveries have been facilitated by tremendous technological advancements in EV-associated research, especially the microfluidics systems. Their pros and cons in the context of characterization of EVs are also extensively discussed in this review. This review also deliberates the role of EVs in normal cell processes and disease conditions, and their application as a diagnostic and therapeutic tool. Finally, we propose future perspectives for EV-related research in stem cell and cancer biology.
Collapse
Affiliation(s)
- Abhimanyu Thakur
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Xiaoshan Ke
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Ya-Wen Chen
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, 90089, USA.,Department of Stem Cell Biology and Regenerative Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Pedram Motallebnejad
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Kui Zhang
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Qizhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong. .,Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. .,HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Pok Fu Lam, Hong Kong.
| | - Huanhuan Joyce Chen
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA. .,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
| |
Collapse
|
|
11
|
Bermick JR, Lincoln PM, Allen RM, Kunkel SL, Schaller MA. Elevated Notch ligands in serum are associated with HIV/TB coinfection. J Clin Tuberc Other Mycobact Dis 2021; 24:100258. [PMID: 34307905 PMCID: PMC8258674 DOI: 10.1016/j.jctube.2021.100258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Objective There is a clear need for improved biomarkers to diagnose HIV/TB coinfection. Although numerous tests can identify the existence of both of these microbes within the host, a parallel assessment of the host response to HIV/TB coinfection may prove as useful confirmation in cases where microbiological tests are inconclusive. To this end we assessed the levels of Notch ligands found in serum samples of patients with TB, HIV or HIV/TB coinfection. The Notch system is involved in almost every stage of development, including the maturation of the immune response. Upon exposure to a pathogen, the innate immune system will increase expression of Notch ligands Delta-like 1 and Delta-like 4. Previous research has demonstrated that Notch ligand expression is increased on monocytes from patients diagnosed with tuberculosis. We hypothesized that if Notch ligands were present in the peripheral blood of individuals diagnosed with TB, they may serve as a novel marker for infection. Design: Serum samples from patients with HIV, TB or HIV/TB coinfection were compared to serum from uninfected individuals to determine levels of DLL1 and DLL4 in a case controlled study. Methods DLL1 and DLL4 were measured by ELISA. Linear regression with post tests were used to determine if levels of DLL1 and DLL4 were increased in individuals with HIV/TB coinfection as compared to individuals infected with either HIV or TB or healthy controls. Results Delta-like 1 and Delta-like 4 were significantly increased in the serum of patients with HIV and HIV/ M. tuberculosis coinfection compared to other groups. Conclusions Assessment of Notch ligands in peripheral blood may enhance the diagnosis of individuals with active TB that are co-infected with HIV. The study will also need to be validated in in a larger cohort.
Collapse
Affiliation(s)
- Jennifer R Bermick
- Department of Pediatrics, Division of Neonatology, University of Iowa, Iowa City, IA, USA.,Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Pamela M Lincoln
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Ronald M Allen
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Steven L Kunkel
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Matthew A Schaller
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.,Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
12
|
The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration. Cell Mol Life Sci 2021; 78:7257-7273. [PMID: 34677645 PMCID: PMC8629791 DOI: 10.1007/s00018-021-03962-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/24/2021] [Accepted: 09/24/2021] [Indexed: 01/17/2023]
Abstract
The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.
Collapse
|
|
13
|
Yao X, Wei W, Wang X, Chenglin L, Björklund M, Ouyang H. Stem cell derived exosomes: microRNA therapy for age-related musculoskeletal disorders. Biomaterials 2019; 224:119492. [PMID: 31557588 DOI: 10.1016/j.biomaterials.2019.119492] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 09/09/2019] [Accepted: 09/11/2019] [Indexed: 12/12/2022]
Abstract
Age-associated musculoskeletal disorders (MSDs) have been historically overlooked by mainstream biopharmaceutical researchers. However, it has now been recognized that stem and progenitor cells confer innate healing capacity for the musculoskeletal system. Current evidence indicates that exosomes are particularly important in this process as they can mediate sequential and reciprocal interactions between cells to initiate and enhance healing. The present review focuses on stem cells (SCs) derived exosomes as a regenerative therapy for treatment of musculoskeletal disorders. We discuss mechanisms involving exosome-mediated transfer of RNAs and how these have been demonstrated in vitro and in vivo to affect signal transduction pathways in target cells. We envision that standardized protocols for stem cell culture as well as for the isolation and characterization of exosomes enable GMP-compliant large-scale production of SCs-derived exosomes. Hence, potential new treatment for age-related degenerative diseases can be seen in the horizon.
Collapse
Affiliation(s)
- Xudong Yao
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China; Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Wei
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China; Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaozhao Wang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China; Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Li Chenglin
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China; Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mikael Björklund
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China
| | - Hongwei Ouyang
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining, China; Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
| |
Collapse
|
|
14
|
Fernandes CFDL, Iglesia RP, Melo-Escobar MI, Prado MB, Lopes MH. Chaperones and Beyond as Key Players in Pluripotency Maintenance. Front Cell Dev Biol 2019; 7:150. [PMID: 31428613 PMCID: PMC6688531 DOI: 10.3389/fcell.2019.00150] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/17/2019] [Indexed: 12/21/2022] Open
Abstract
Pluripotency is orchestrated by distinct players and chaperones and their partners have emerged as pivotal molecules in proteostasis control to maintain stemness. The proteostasis network consists of diverse interconnected pathways that function dynamically according to the needs of the cell to quality control and maintain protein homeostasis. The proteostasis machinery of pluripotent stem cells (PSCs) is finely adjusted in response to distinct stimuli during cell fate commitment to determine successful organism development. Growing evidence has shown different classes of chaperones regulating crucial cellular processes in PSCs. Histones chaperones promote proper nucleosome assembly and modulate the epigenetic regulation of factors involved in PSCs’ rapid turnover from pluripotency to differentiation. The life cycle of pluripotency proteins from synthesis and folding, transport and degradation is finely regulated by chaperones and co-factors either to maintain the stemness status or to cell fate commitment. Here, we summarize current knowledge of the chaperone network that govern stemness and present the versatile role of chaperones in stem cells resilience. Elucidation of the intricate regulation of pluripotency, dissecting in detail molecular determinants and drivers, is fundamental to understanding the properties of stem cells in order to provide a reliable foundation for biomedical research and regenerative medicine.
Collapse
Affiliation(s)
- Camila Felix de Lima Fernandes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rebeca Piatniczka Iglesia
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Isabel Melo-Escobar
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mariana Brandão Prado
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marilene Hohmuth Lopes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
15
|
Shi C, Ulke-Lemée A, Deng J, Batulan Z, O'Brien ER. Characterization of heat shock protein 27 in extracellular vesicles: a potential anti-inflammatory therapy. FASEB J 2018; 33:1617-1630. [PMID: 30188755 DOI: 10.1096/fj.201800987r] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Previously, we reported that elevated serum levels of heat shock protein 27 (HSP27) are predictive of a lower risk of having a heart attack, stroke, or death from cardiovascular disease. Moreover, augmenting HSP27 (or the murine ortholog, HSP25) attenuated experimental atherogenesis, reduced inflammation, and lowered cholesterol levels. Recently, we noted that HSP27 activates NF-κB via TLR-4, resulting in attenuation of plaque inflammation; however, the precise anti-atherosclerosis mechanisms mediated by extracellular HSP27 are incompletely understood. Our purpose in this study was to investigate the existence of HSP27 in extracellular vesicles (EVs) and whether HSP27 elicited atheroprotective effects on target cells. Here, we provide evidence that HSP27 localizes to EVs derived from THP-1 cells using transmission electron microscopy (TEM) and immunogold labeling, Western blotting, ELISA, and fluorescence-activated cell sorting. TEM imaging indicated that HSP27 is found at the exosomal membrane. Multiple reactor monitor-mass spectrometric analysis of large vesicles, which included microparticles and exosomes, isolated from human plasma, also led to detection of HSP27 using the unique signature peptide, R.LFDQAFGLPR.L. Studies using THP-1 and human embryonic kidney cells show that HSP27-laden exosomes significantly stimulated NF-κB activation ( P < 0.001) and release of IL-10 ( P < 0.0001), suggesting that HSP27 may be important exosomal cargo with beneficial anti-inflammatory effects.-Shi, C., Ulke-Lemée, A., Deng, J., Batulan, Z., O'Brien, E. R. Characterization of heat shock protein 27 in extracellular vesicles: a potential anti-inflammatory therapy.
Collapse
Affiliation(s)
- Chunhua Shi
- Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Annegret Ulke-Lemée
- Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jingti Deng
- Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Zarah Batulan
- Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Edward R O'Brien
- Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| |
Collapse
|
|
16
|
Cruz L, Romero JAA, Iglesia RP, Lopes MH. Extracellular Vesicles: Decoding a New Language for Cellular Communication in Early Embryonic Development. Front Cell Dev Biol 2018; 6:94. [PMID: 30211159 PMCID: PMC6121069 DOI: 10.3389/fcell.2018.00094] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 07/30/2018] [Indexed: 01/08/2023] Open
Abstract
The blastocyst inner cell mass (ICM) that gives rise to a whole embryo in vivo can be derived and cultured in vitro as embryonic stem cells (ESCs), which retain full developmental potential. ICM cells receive, from diverse sources, complex molecular and spatiotemporal signals that orchestrate the finely-tuned processes associated with embryogenesis. Those instructions come, continuously, from themselves and from surrounding cells, such as those present in the trophectoderm and primitive endoderm (PrE). A key component of the ICM niche are the extracellular vesicles (EVs), produced by distinct cell types, that carry and transfer key molecules that regulate target cells and modulate cell renewal or cell fate. A growing number of studies have demonstrated the extracellular circulation of morphogens, a group of classical regulators of embryo development, are carried by EVs. miRNAs are also an important cargo of the EVs that have been implicated in tissue morphogenesis and have gained special attention due to their ability to regulate protein expression through post-transcriptional modulation, thereby influencing cell phenotype. This review explores the emerging evidence supporting the role of EVs as an additional mode of intercellular communication in early embryonic and ESCs differentiation.
Collapse
Affiliation(s)
- Lilian Cruz
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jenny A A Romero
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rebeca P Iglesia
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marilene H Lopes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
17
|
From intra- to extracellular vesicles: extracellular vesicles in developmental signalling. Essays Biochem 2018; 62:215-223. [DOI: 10.1042/ebc20180001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 03/02/2018] [Accepted: 03/06/2018] [Indexed: 12/12/2022]
Abstract
Signalling from cell-to-cell is fundamental for determining differentiation and patterning. This communication can occur between adjacent and distant cells. Extracellular vesicles (EVs) are membrane-based structures thought to facilitate the long-distance movement of signalling molecules. EVs have recently been found to allow the transport of two major developmental signalling pathways: Hedgehog and Wnt. These signalling molecules undergo crucial post-translational lipid modifications, which anchor them to membranes and impede their free release into the extracellular space. Preparation of these ligands in EVs involves intracellular vesicle sorting in an endocytosis-dependent recycling process before secretion. In the present review, we discuss the most recent advances with regard to EV involvement in developmental signalling at a distance. We focus on the role of the protein complexes involved in EV genesis, and provide a comprehensive perspective of the contribution of these complexes to intracellular vesicle sorting of developmental signals for their extracellular secretion, reception and transduction.
Collapse
|