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Title: Divergent levels of CD112 and INKA1 define a distinct subset of human long-term hematopoietic stem cells

The data provided here was critical in establishing that human long-term hematopoietic stem cells (LT-HSC), previously described as the most primitive HSC population, is actually composed of distinct subsets that can be prospectively isolated. Via mechanistic studies centering around the Rho-GTPase effector kinase PAK4 and its inhibitor INKA1, we identified the immune checkpoint ligand CD112 as a marker for hematopoietic stem and progenitor cells, that is highest expressed on LT-HSC. More importantly, CD112 can be used to stratify functionally distinct subsets within LT-HSC: In response to regeneration-mediated stress, the CD112low subset exhibits a transient restraint (termed latency) before contributing to hematopoietic reconstitution, while the CD112high subset is primed to respond rapidly. High resolution RNA-seq of the CD112 surface expression spectrum within rare LT-HSC subsets (human umbilical cord blood) demonstrated that more genes are differentially upregulated in the deeper quiescent and less metabolic active subset. Genes enriched in this subset centre around cell adhesion and Rho-GTPase signaling. This is in agreement with the scRNAseq data from human G-CSF mobilized peripheral blood (mPB) generated here that was used as an model of in vivo activation/priming revealing via RNA-velocity and pseudo-time analysis that INKA1high versus PAK4high, CDK6high and CD112high enrichment are either detected early or late in diffusion pseudotime indicative of quiescent versus primed cell status, respectively. RNAseq following INKA1 overexpression in LT-HSC and ST-HSC revealed by GSEA an overall stemness preserving phenotype and particularly in LT-HSC, but not in short-term HSC (ST-HSC), suppression of transcriptional programs linked to activation. Collectively, our data decipher the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that integrates quiescence control with HSC fate choices to preserve a stem cell reservoir.

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Access to data generated by UHN is made available by completing the data access agreement for review by the data access committee and will be granted to qualified investigators for appropriate use.

DATA ACCESS AGREEMENT These terms and conditions govern access to the managed access datasets (details of which are set out in Appendix I) to which the User Institution has requested access. The User Institution agrees to be bound by these terms and conditions. Definitions Authorised Personnel: The individuals at the User Institution to whom the Data Access Committee (DAC) grants access to the Data. This includes the User, the individuals listed in Appendix II and any other individuals for whom the User Institution subsequently requests access to the Data. Details of the initial Authorised Personnel are set out in Appendix II. Data: The managed access datasets to which the User Institution has requested access. Data Producers: The Principal Investigator and the collaborators listed in Appendix I responsible for the development, organisation, and oversight of these Data. External Collaborator: A collaborator of the User, working for an institution other than the User Institution. Project: The project for which the User Institution has requested access to these Data. A description of the Project is set out in Appendix II. Publications: Includes, without limitation, articles published in print journals, electronic journals, reviews, books, posters and other written and verbal presentations of research. Research Participant: An individual whose data form part of these Data. Research Purposes: Shall mean research that is seeking to advance the understanding of genetics and genomics, including the treatment of disorders, and work on statistical methods that may be applied to such research. User: The principal investigator for the Project. User Institution(s): The Institution that has requested access to the Data. University Health Network: The University Health Network (UHN) is the largest clinical and research hospital in Canada. UHN is affiliated with the University of Toronto and is a member of the Toronto Academic Health Science Network. 1. The User Institution agrees to only use these Data for the purpose of the Project (described in Appendix II) and only for Research Purposes. The User Institution further agrees that it will only use these Data for Research Purposes which are within the limitations (if any) set out in Appendix I. 2. The User Institution agrees to preserve, at all times, the confidentiality of these Data. In particular, it undertakes not to use, or attempt to use these Data to compromise or otherwise infringe the confidentiality of information on Research Participants. Without prejudice to the generality of the foregoing, the User Institution agrees to use at least the measures set out in Appendix I to protect these Data. 3. The User Institution agrees to protect the confidentiality of Research Participants in any research papers or publications that they prepare by taking all reasonable care to limit the possibility of identification. 4. The User Institution agrees not to link or combine these Data to other information or archived data available in a way that could re-identify the Research Participants, even if access to that data has been formally granted to the User Institution or is freely available without restriction. 5. The User Institution agrees only to transfer or disclose these Data, in whole or part, or any material derived from these Data, to the Authorised Personnel. Should the User Institution wish to share these Data with an External Collaborator, the External Collaborator must complete a separate application for access to these Data. 6. The User Institution agrees that the Data Producers, and all other parties involved in the creation, funding or protection of these Data: a) make no warranty or representation, express or implied as to the accuracy, quality or comprehensiveness of these Data; b) exclude to the fullest extent permitted by law all liability for actions, claims, proceedings, demands, losses (including but not limited to loss of profit), costs, awards damages and payments made by the Recipient that may arise (whether directly or indirectly) in any way whatsoever from the Recipient’s use of these Data or from the unavailability of, or break in access to, these Data for whatever reason and; c) bear no responsibility for the further analysis or interpretation of these Data. 7. The User Institution agrees to follow the Fort Lauderdale Guidelines (http://www.wellcome.ac.uk/stellent/groups/corporatesite/@policy_communications/documents/web_document/wtd003207.pdf ) and the Toronto Statement (http://www.nature.com/nature/journal/v461/n7261/full/461168a.html). This includes but is not limited to recognising the contribution of the Data Producers and including a proper acknowledgement in all reports or publications resulting from the use of these Data. 8. The User Institution agrees to follow the Publication Policy in Appendix III. This includes respecting the moratorium period for the Data Producers to publish the first peer-reviewed report describing and analysing these Data. 9. The User Institution agrees not to make intellectual property claims on these Data and not to use intellectual property protection in ways that would prevent or block access to, or use of, any element of these Data, or conclusion drawn directly from these Data. 10. The User Institution can elect to perform further research that would add intellectual and resource capital to these data and decide to obtain intellectual property rights on these downstream discoveries. In this case, the User Institution agrees to implement licensing policies that will not obstruct further research and to follow the U.S. National Institutes of Health Best Practices for the Licensing of Genomic Inventions (2005) (https://www.icgc.org/files/daco/NIH_BestPracticesLicensingGenomicInventions_2005_en.pdf ) in conformity with the Organisation for Economic Co-operation and Development Guidelines for the Licensing of the Genetic Inventions (2006) (http://www.oecd.org/science/biotech/36198812.pdf ). 11. The User Institution agrees to destroy/discard the Data held, once it is no longer used for the Project, unless obliged to retain the data for archival purposes in conformity with audit or legal requirements. 12. The User Institution will notify the DAC within 30 days of any changes or departures of Authorised Personnel. 13. The User Institution will notify the DAC prior to any significant changes to the protocol for the Project. 14. The User Institution will notify the DAC as soon as it becomes aware of a breach of the terms or conditions of this agreement. 15. The DAC may terminate this agreement by written notice to the User Institution. If this agreement terminates for any reason, the User Institution will be required to destroy any Data held, including copies and backup copies. This clause does not prevent the User Institution from retaining these data for archival purpose in conformity with audit or legal requirements. 16. The User Institution accepts that it may be necessary for the Data Producers to alter the terms of this agreement from time to time. In the event that changes are required, the Data Producers or their appointed agent will contact the User Institution to inform it of the changes and the User Institution may elect to accept the changes or terminate the agreement. 17. If requested, the User Institution will allow data security and management documentation to be inspected to verify that it is complying with the terms of this agreement. 18. The User Institution agrees to distribute a copy of these terms to the Authorised Personnel. The User Institution will procure that the Authorised Personnel comply with the terms of this agreement. 19. This agreement (and any dispute, controversy, proceedings or claim of whatever nature arising out of this agreement or its formation) shall be construed, interpreted and governed by the laws of the province of Ontario and PHIPA. Agreed for User Institution Signature: Name: Title: Date: Principal Investigator I confirm that I have read and understood this Agreement. Signature: Name: Title: Date: Agreed for The Data Access Committee Signature: Name: Title: Date: APPENDIX I – DATASET DETAILS APPENDIX II ––PROJECT DETAILS APPENDIX III –– PUBLICATION POLICY

Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001004768 Other
EGAS00001004769 Other
EGAS00001005121 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00004824069 fastq.gz 4.7 GB
EGAF00004824070 fastq.gz 4.8 GB
EGAF00004824071 fastq.gz 5.2 GB
EGAF00004824072 fastq.gz 5.3 GB
EGAF00004824073 fastq.gz 4.8 GB
EGAF00004824074 fastq.gz 4.9 GB
EGAF00004824075 fastq.gz 5.2 GB
EGAF00004824076 fastq.gz 5.3 GB
EGAF00004824077 fastq.gz 5.3 GB
EGAF00004824078 fastq.gz 5.3 GB
EGAF00004824079 fastq.gz 5.0 GB
EGAF00004824080 fastq.gz 5.2 GB
EGAF00004824081 fastq.gz 5.2 GB
EGAF00004824082 fastq.gz 5.3 GB
EGAF00004824083 fastq.gz 5.2 GB
EGAF00004824084 fastq.gz 5.4 GB
EGAF00004824085 fastq.gz 7.2 GB
EGAF00004824086 fastq.gz 7.2 GB
EGAF00004824087 fastq.gz 6.8 GB
EGAF00004824088 fastq.gz 6.8 GB
EGAF00004824089 fastq.gz 6.4 GB
EGAF00004824090 fastq.gz 6.2 GB
EGAF00004824091 fastq.gz 11.1 GB
EGAF00004824092 fastq.gz 11.0 GB
EGAF00004824093 fastq.gz 6.4 GB
EGAF00004824094 fastq.gz 6.4 GB
EGAF00004824095 fastq.gz 6.1 GB
EGAF00004824096 fastq.gz 6.2 GB
EGAF00004824097 fastq.gz 6.8 GB
EGAF00004824098 fastq.gz 6.9 GB
EGAF00004824099 fastq.gz 5.9 GB
EGAF00004824100 fastq.gz 5.9 GB
EGAF00004824101 fastq.gz 6.9 GB
EGAF00004824102 fastq.gz 6.8 GB
EGAF00004824103 fastq.gz 386.1 MB
EGAF00004824104 fastq.gz 583.3 MB
EGAF00004824105 fastq.gz 410.3 MB
EGAF00004824106 fastq.gz 616.6 MB
EGAF00004824107 fastq.gz 407.5 MB
EGAF00004824108 fastq.gz 612.9 MB
EGAF00004824109 fastq.gz 385.5 MB
EGAF00004824110 fastq.gz 568.4 MB
EGAF00004824111 fastq.gz 383.3 MB
EGAF00004824112 fastq.gz 565.3 MB
EGAF00004824113 fastq.gz 378.5 MB
EGAF00004824114 fastq.gz 565.3 MB
EGAF00004824115 fastq.gz 376.0 MB
EGAF00004824116 fastq.gz 562.0 MB
EGAF00004824117 fastq.gz 359.5 MB
EGAF00004824118 fastq.gz 536.2 MB
EGAF00004824119 fastq.gz 357.7 MB
EGAF00004824120 fastq.gz 533.9 MB
EGAF00004824121 fastq.gz 372.6 MB
EGAF00004824122 fastq.gz 563.9 MB
EGAF00004824123 fastq.gz 370.2 MB
EGAF00004824124 fastq.gz 560.8 MB
EGAF00004824125 fastq.gz 393.9 MB
EGAF00004824126 fastq.gz 586.3 MB
EGAF00004824127 fastq.gz 391.3 MB
EGAF00004824128 fastq.gz 582.9 MB
EGAF00004824129 fastq.gz 389.2 MB
EGAF00004824130 fastq.gz 565.9 MB
EGAF00004824131 fastq.gz 396.5 MB
EGAF00004824132 fastq.gz 581.5 MB
EGAF00004824133 fastq.gz 477.7 MB
EGAF00004824134 fastq.gz 692.2 MB
EGAF00004824135 fastq.gz 488.6 MB
EGAF00004824136 fastq.gz 713.9 MB
EGAF00004824137 fastq.gz 482.5 MB
EGAF00004824138 fastq.gz 705.5 MB
EGAF00004824139 fastq.gz 493.5 MB
EGAF00004824140 fastq.gz 727.6 MB
EGAF00004824141 fastq.gz 829.6 MB
EGAF00004824142 fastq.gz 1.2 GB
EGAF00004824143 fastq.gz 325.4 MB
EGAF00004824144 fastq.gz 475.9 MB
EGAF00004824145 fastq.gz 332.8 MB
EGAF00004824146 fastq.gz 491.1 MB
EGAF00004824147 fastq.gz 574.8 MB
EGAF00004824148 fastq.gz 841.8 MB
EGAF00004824149 fastq.gz 588.6 MB
EGAF00004824150 fastq.gz 869.2 MB
EGAF00004824151 fastq.gz 274.4 MB
EGAF00004824152 fastq.gz 398.0 MB
EGAF00004824153 fastq.gz 279.5 MB
EGAF00004824154 fastq.gz 409.1 MB
EGAF00004824155 fastq.gz 505.4 MB
EGAF00004824156 fastq.gz 740.0 MB
EGAF00004824157 fastq.gz 516.6 MB
EGAF00004824158 fastq.gz 762.4 MB
EGAF00004824159 fastq.gz 460.2 MB
EGAF00004824160 fastq.gz 667.9 MB
EGAF00004824161 fastq.gz 470.3 MB
EGAF00004824162 fastq.gz 688.0 MB
EGAF00005097174 fastq.gz 2.0 GB
EGAF00005097175 fastq.gz 2.1 GB
EGAF00005097176 fastq.gz 2.5 GB
EGAF00005097177 fastq.gz 2.6 GB
EGAF00005097178 fastq.gz 2.0 GB
EGAF00005097179 fastq.gz 2.1 GB
EGAF00005097180 fastq.gz 2.2 GB
EGAF00005097181 fastq.gz 2.3 GB
EGAF00005097182 fastq.gz 2.5 GB
EGAF00005097183 fastq.gz 2.5 GB
104 Files (263.8 GB)