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Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
The E–Id Protein Axis Modulates the Activities of the PI3K–AKT–Mtorc1
Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The E–Id protein axis modulates the activities of the PI3K–AKT–mTORC1– Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis Masaki Miyazaki,1,8 Kazuko Miyazaki,1,8 Shuwen Chen,1 Vivek Chandra,1 Keisuke Wagatsuma,2 Yasutoshi Agata,2 Hans-Reimer Rodewald,3 Rintaro Saito,4 Aaron N. Chang,5 Nissi Varki,6 Hiroshi Kawamoto,7 and Cornelis Murre1 1Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; 2Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan; 3Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany; 4Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA; 5Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA; 6Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA; 7Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naı¨ve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. -
1 AGING Supplementary Table 2
SUPPLEMENTARY TABLES Supplementary Table 1. Details of the eight domain chains of KIAA0101. Serial IDENTITY MAX IN COMP- INTERFACE ID POSITION RESOLUTION EXPERIMENT TYPE number START STOP SCORE IDENTITY LEX WITH CAVITY A 4D2G_D 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ B 4D2G_E 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ C 6EHT_D 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ D 6EHT_E 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ E 6GWS_D 41-72 41 72 100 100 3.2Å PCNA X-RAY DIFFRACTION √ F 6GWS_E 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ G 6GWS_F 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ H 6IIW_B 2-11 2 11 100 100 1.699Å UHRF1 X-RAY DIFFRACTION √ www.aging-us.com 1 AGING Supplementary Table 2. Significantly enriched gene ontology (GO) annotations (cellular components) of KIAA0101 in lung adenocarcinoma (LinkedOmics). Leading Description FDR Leading Edge Gene EdgeNum RAD51, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, CENPW, HJURP, NDC80, CDCA5, NCAPH, BUB1, ZWILCH, CENPK, KIF2C, AURKA, CENPN, TOP2A, CENPM, PLK1, ERCC6L, CDT1, CHEK1, SPAG5, CENPH, condensed 66 0 SPC24, NUP37, BLM, CENPE, BUB3, CDK2, FANCD2, CENPO, CENPF, BRCA1, DSN1, chromosome MKI67, NCAPG2, H2AFX, HMGB2, SUV39H1, CBX3, TUBG1, KNTC1, PPP1CC, SMC2, BANF1, NCAPD2, SKA2, NUP107, BRCA2, NUP85, ITGB3BP, SYCE2, TOPBP1, DMC1, SMC4, INCENP. RAD51, OIP5, CDK1, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, ESCO2, CENPW, HJURP, TTK, NDC80, CDCA5, BUB1, ZWILCH, CENPK, KIF2C, AURKA, DSCC1, CENPN, CDCA8, CENPM, PLK1, MCM6, ERCC6L, CDT1, HELLS, CHEK1, SPAG5, CENPH, PCNA, SPC24, CENPI, NUP37, FEN1, chromosomal 94 0 CENPL, BLM, KIF18A, CENPE, MCM4, BUB3, SUV39H2, MCM2, CDK2, PIF1, DNA2, region CENPO, CENPF, CHEK2, DSN1, H2AFX, MCM7, SUV39H1, MTBP, CBX3, RECQL4, KNTC1, PPP1CC, CENPP, CENPQ, PTGES3, NCAPD2, DYNLL1, SKA2, HAT1, NUP107, MCM5, MCM3, MSH2, BRCA2, NUP85, SSB, ITGB3BP, DMC1, INCENP, THOC3, XPO1, APEX1, XRCC5, KIF22, DCLRE1A, SEH1L, XRCC3, NSMCE2, RAD21. -
Methylome and Transcriptome Maps of Human Visceral and Subcutaneous
www.nature.com/scientificreports OPEN Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal Received: 9 April 2019 Accepted: 11 June 2019 key epigenetic diferences at Published: xx xx xxxx developmental genes Stephen T. Bradford1,2,3, Shalima S. Nair1,3, Aaron L. Statham1, Susan J. van Dijk2, Timothy J. Peters 1,3,4, Firoz Anwar 2, Hugh J. French 1, Julius Z. H. von Martels1, Brodie Sutclife2, Madhavi P. Maddugoda1, Michelle Peranec1, Hilal Varinli1,2,5, Rosanna Arnoldy1, Michael Buckley1,4, Jason P. Ross2, Elena Zotenko1,3, Jenny Z. Song1, Clare Stirzaker1,3, Denis C. Bauer2, Wenjia Qu1, Michael M. Swarbrick6, Helen L. Lutgers1,7, Reginald V. Lord8, Katherine Samaras9,10, Peter L. Molloy 2 & Susan J. Clark 1,3 Adipocytes support key metabolic and endocrine functions of adipose tissue. Lipid is stored in two major classes of depots, namely visceral adipose (VA) and subcutaneous adipose (SA) depots. Increased visceral adiposity is associated with adverse health outcomes, whereas the impact of SA tissue is relatively metabolically benign. The precise molecular features associated with the functional diferences between the adipose depots are still not well understood. Here, we characterised transcriptomes and methylomes of isolated adipocytes from matched SA and VA tissues of individuals with normal BMI to identify epigenetic diferences and their contribution to cell type and depot-specifc function. We found that DNA methylomes were notably distinct between diferent adipocyte depots and were associated with diferential gene expression within pathways fundamental to adipocyte function. Most striking diferential methylation was found at transcription factor and developmental genes. Our fndings highlight the importance of developmental origins in the function of diferent fat depots. -
Estradiol-Regulated Micrornas Control Estradiol Response in Breast Cancer Cells Poornima Bhat-Nakshatri1, Guohua Wang2, Nikail R
4850–4861 Nucleic Acids Research, 2009, Vol. 37, No. 14 Published online 14 June 2009 doi:10.1093/nar/gkp500 Estradiol-regulated microRNAs control estradiol response in breast cancer cells Poornima Bhat-Nakshatri1, Guohua Wang2, Nikail R. Collins1, Michael J. Thomson3, Tim R. Geistlinger4, Jason S. Carroll4, Myles Brown4, Scott Hammond3, Edward F. Srour2, Yunlong Liu2 and Harikrishna Nakshatri1,5,* 1Department of Surgery, 2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 3Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 4Department of Medical Oncology, Dana-Farber Medical School, Harvard Medical School, Boston, MA and 5Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA Received May 4, 2009; Revised May 22, 2009; Accepted May 24, 2009 ABSTRACT INTRODUCTION Estradiol (E2) regulates gene expression at the Estradiol (E2) controls several biological processes by transcriptional level by functioning as a ligand for functioning as a ligand for nuclear receptors estrogen estrogen receptor alpha (ERa) and estrogen receptor receptor alpha (ERa) and beta (ERb) (1). ERs may par- beta (ERb). E2-inducible proteins c-Myc and E2Fs are ticipate in the genomic (transcriptional) and non-genomic required for optimal ERa activity and secondary actions of E2 (1,2). The genomic action involves binding of ERa to the regulatory regions of target genes either estrogen responses, respectively. We show that directly or through protein–protein interaction. DNA- E2 induces 21 microRNAs and represses seven bound ERa then recruits various co-regulatory molecules microRNAs in MCF-7 breast cancer cells; these to induce chromatin modifications that either increase or microRNAs have the potential to control 420 decrease the level of target gene transcription. -
Supplemental Table 1. Primers and Probes for RT-Pcrs
Supplemental Table 1. Primers and probes for RT-PCRs Gene Direction Sequence Quantitative RT-PCR E2F1 Forward Primer 5’-GGA TTT CAC ACC TTT TCC TGG AT-3’ Reverse Primer 5’-CCT GGA AAC TGA CCA TCA GTA CCT-3’ Probe 5’-FAM-CGA GCT GGC CCA CTG CTC TCG-TAMRA-3' E2F2 Forward Primer 5'-TCC CAA TCC CCT CCA GAT C-3' Reverse Primer 5'-CAA GTT GTG CGA TGC CTG C-3' Probe 5' -FAM-TCC TTT TGG CCG GCA GCC G-TAMRA-3' E2F3a Forward Primer 5’-TTT AAA CCA TCT GAG AGG TAC TGA TGA-3’ Reverse Primer 5’-CGG CCC TCC GGC AA-3’ Probe 5’-FAM-CGC TTT CTC CTA GCT CCA GCC TTC G-TAMRA-3’ E2F3b Forward Primer 5’-TTT AAA CCA TCT GAG AGG TAC TGA TGA-3’ Reverse Primer 5’-CCC TTA CAG CAG CAG GCA A-3’ Probe 5’-FAM-CGC TTT CTC CTA GCT CCA GCC TTC G-TAMRA-3’ IRF-1 Forward Primer 5’-TTT GTA TCG GCC TGT GTG AAT G-3’ Reverse Primer 5’-AAG CAT GGC TGG GAC ATC A-3’ Probe 5’-FAM-CAG CTC CGG AAC AAA CAG GCA TCC TT-TAMRA-3' IRF-2 Forward Primer 5'-CGC CCC TCG GCA CTC T-3' Reverse Primer 5'-TCT TCC TAT GCA GAA AGC GAA AC-3' Probe 5'-FAM-TTC ATC GCT GGG CAC ACT ATC AGT-TAMRA-3' TBP Forward Primer 5’-CAC GAA CCA CGG CAC TGA TT-3’ Reverse Primer 5’-TTT TCT TGC TGC CAG TCT GGA C-3’ Probe 5’-FAM-TGT GCA CAG GAG CCA AGA GTG AAG A-BHQ1-3’ Primers and Probes for quantitative RT-PCRs were designed using the computer program “Primer Express” (Applied Biosystems, Foster City, CA, USA). -
Integrative Bulk and Single-Cell Profiling of Premanufacture T-Cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-Cell Therapy
Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 RESEARCH ARTICLE Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy Gregory M. Chen1, Changya Chen2,3, Rajat K. Das2, Peng Gao2, Chia-Hui Chen2, Shovik Bandyopadhyay4, Yang-Yang Ding2,5, Yasin Uzun2,3, Wenbao Yu2, Qin Zhu1, Regina M. Myers2, Stephan A. Grupp2,5, David M. Barrett2,5, and Kai Tan2,3,5 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 ABSTRACT The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. -
A Pathologic Link Between Wilms Tumor Suppressor Gene, WT1, And
Volume 10 Number 1 January 2008 pp. 69–78 69 www.neoplasia.com RESEARCH ARTICLE † Marianne K.-H. Kim*, Jacqueline M. Mason , A Pathologic Link between Wilms ‡ § Chi-Ming Li , Windy Berkofsky-Fessler , ∥ WT1 Le Jiang , Divaker Choubey¶, Paul E. Grundy#, Tumor Suppressor Gene, , ∥ and IFI161,2 Benjamin Tycko and Jonathan D. Licht* *Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA; †The Campbell Family Institute for Breast Cancer Research at the Ontario, Cancer Institute, Ontario, Canada; ‡Translational Medicine, Amgen, Thousand Oaks, CA, USA; §Section of Bioinformatics, Genetics and Genomics, Hoffmann-La Roche Inc, Nutley, NJ, USA; ∥Institute for Cancer Genetics and Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA; ¶University of Cincinnati, Cincinnati, OH, USA; #University of Alberta, Alberta, Canada Abstract The Wilms tumor gene (WT1) is mutated or deleted in patients with heredofamilial syndromes associated with the development of Wilms tumors, but is infrequently mutated in sporadic Wilms tumors. By comparing the micro- array profiles of syndromic versus sporadic Wilms tumors and WT1-inducible Saos-2 osteosarcoma cells, we iden- tified interferon-inducible protein 16 (IFI16), a transcriptional modulator, as a differentially expressed gene and a candidate WT1 target gene. WT1 induction in Saos-2 osteosarcoma cells led to strong induction of IFI16 expression and its promoter activity was responsive to the WT1 protein. Immunohistochemical analysis showed that IFI16 and WT1 colocalized in WT1-replete Wilms tumors, but not in normal human midgestation fetal kidneys, suggesting that the ability of WT1 to regulate IFI16 in tumors represented an aberrant pathologic relationship. -
1.1.4.1. Tumour Suppressor Genes
To my Mother and Father Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning. Albert Einstein Inhibition of Tumourigenicity of Small Cell Lung Cancer by Simultaneous Suppression of Id1 and Id3 Expression Danqing Chen ABSTRACT Inhibitor of DNA binding (Id) proteins are a group of transcription factors belonging to the basic helix-loop-helix (bHLH) family and play a wide range of roles in differentiation, proliferation and cell cycle progression. Id proteins act as negative dominant regulators of other bHLH factors by making dimers to these factors to prevent them from binding to E-box of DNA and, hence, to inhibit transcription of target genes. In this work, we first established SCLC cell line N417-derived sublines expressing reduced levels of Id1 and Id3 by transfection of a single vector constructed to co-express two shRNAs simultaneously. Then we investigated the effect of either singly or jointly suppressed Id1 or Id3 on tumourigenicity of SCLC cells in vitro and in vivo. The molecular mechanisms involved in the functional roles of Id1 and Id3 were also assessed. Id1-suppressed cells and Id1 and Id3 double knockdown cells produced significant reductions in proliferation rate by more than 1.4- and 3.9-fold respectively when compared with the control. Soft agar assay showed the number of colonies produced by Id1-suppressed cells and Id1 and Id3 double knockdown cells were reduced by more than 13.7- and 233-fold respectively compared with the control. The suppression effect was also observed in the invasion assay which showed that Id1-suppressed cells and Id1 and Id3 double knockdown cells produced more than 1.7- and 4.6- fold reduction respectively in relative invasiveness. -
Mammalian Atypical E2fs Link Endocycle Control to Cancer
Mammalian Atypical E2Fs Link Endocycle Control to Cancer DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Hui-Zi Chen Graduate Program in Integrated Biomedical Science Program The Ohio State University 2011 Dissertation Committee: Gustavo Leone, PhD, Advisor Michael Ostrowski, PhD Clay Marsh, MD Tsonwin Hai, PhD Kathryn Wikenheiser-Brokamp, MD PhD Copyright by Hui-Zi Chen 2011 Abstract The endocycle is a developmentally programmed variant cell cycle consisting of successive S (DNA synthesis) and G (Gap) phases without an intervening M phase or cytokinesis. As a consequence of the regulated “decoupling” of DNA replication and mitosis, which are two central processes of the traditional cell division program, endocycling cells acquire highly polyploid genomes after having undergone multiple rounds of whole genome reduplication. Although essential for metazoan development, relatively little is known about the regulation of endocycle or its physiologic role in higher vertebrates such as the mammal. A substantial body of work in the model organism Drosophila melanogaster has demonstrated an important function for dE2Fs in the control of endocycle. Genetic studies showed that both endocycle initiation and progression is severely disrupted by altering the expression of the fly E2F activator (dE2F1) or repressor (dE2F2). In mammals, the E2F family is comprised of nine structurally related proteins, encoded by eight distinct genes, that can be classified into transcriptional activators (E2f1, E2f2, E2f3a and E2f3b) or repressors (E2f4, E2f5, E2f6, E2f7 and E2f8). The repressor subclass may then be further divided into canonical (E2f4, E2f5 and E2f6) or atypical E2fs (E2f7 and E2f8). -
Human Pluripotent Stem Cell-Derived Ectomesenchymal Stromal Cells Promote More Robust Functional Recovery Than Umbilical Cord-De
Human pluripotent stem cell-derived ectomesenchymal stromal cells promote more robust functional recovery than umbilical cord-derived mesenchymal stromal cells after hypoxic- ischaemic brain damage Jiawei Huang1,3*, Kin Pong U1,3*, Fuyuan Yang1, Zeyuan Ji1, Jiacheng Lin1,3, Zhihui Weng1, Lai Ling Tsang1,3, Tobias D Merson5, Ye Chun Ruan6, Chao Wan1,3, Gang Li2, Xiaohua Jiang1,3,4 1School of Biomedical Sciences, 2Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China. 3School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China. 4Sichuan University – The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan, China. 5Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. 6Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China. Running Title: Human ectomesenchymal stromal cells promote functional recovery in a rat HIE model *Corresponding author: Prof. Xiaohua JIANG, Email: [email protected] Address: Room 409A, Lo Kwee Seong Integrated Biomedical Sciences Building, Area 39, The Chinese University of Hong Kong, Shatin. Keywords: HIE, ectomesenchymal stromal cells, brain damage, regeneration, paracrine, ERK Abstract: Aims: Hypoxic-ischaemic encephalopathy (HIE) is one of the most serious complications in neonates and infants. Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment avenue for HIE. However, despite its enormous potential, the clinical application of MSCs is limited by cell heterogeneity, low isolation efficiency and unpredictable effectiveness. In this study, we examined the therapeutic effects and underlying mechanisms of human pluripotent stem cell-derived ectomesenchymal stromal cells (hPSC-EMSCs) in a rat model of HIE.