Abstract
Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future.
| Original language | English |
|---|---|
| Pages (from-to) | 2745-2759 |
| Number of pages | 15 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 7 |
| DOIs | |
| State | Published - 2019 |
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Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells. / Karpova, Darja; Rettig, Michael P.; Ritchey, Julie et al.
In: Journal of Clinical Investigation, Vol. 129, No. 7, 2019, p. 2745-2759.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells
AU - Karpova, Darja
AU - Rettig, Michael P.
AU - Ritchey, Julie
AU - Cancilla, Daniel
AU - Christ, Stephanie
AU - Gehrs, Leah
AU - Chendamarai, Ezhilarasi
AU - Evbuomwan, Moses O.
AU - Holt, Matthew
AU - Zhang, Jingzhu
AU - Abou-Ezzi, Grazia
AU - Celik, Hamza
AU - Wiercinska, Eliza
AU - Yang, Wei
AU - Gao, Feng
AU - Eissenberg, Linda G.
AU - Heier, Richard F.
AU - Arnett, Stacy D.
AU - Meyers, Marvin J.
AU - Prinsen, Michael J.
AU - Griggs, David W.
AU - Trumpp, Andreas
AU - Ruminski, Peter G.
AU - Morrow, Dwight M.
AU - Bonig, Halvard B.
AU - Link, Daniel C.
AU - DiPersio, John F.
N1 - Funding Information: DK is a past scholar of the German Academic Exchange Service (postdoctoral fellowship ID: 57054578, 2014-2016). MPR is supported by the National Institutes of Health, National Cancer Institute (R50 CA211466), an Alvin J. Siteman Cancer Center, Siteman Investment Program award that is supported by The Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, the Barnard Trust, and a National Cancer Institute Cancer Center support grant (P30 CA091842). HC was supported by the American Society of Hematology and the Edward P. Evans Foundation. HB is a member of LOEWE Cell and Gene Therapy Frankfurt faculty, funded by the Hessian Ministry of Higher Education, Research and the Arts (III L 4- 518/17.004, 2010-2018). JFD is supported by grants from the National Institutes of Health, National Cancer Institute (U54 CA199092, R01 CA152329, and R35 CA210084). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Genome Technology Access Center is partially supported by NCI Cancer Center support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Siteman Flow Cytometry Core. The Siteman Cancer Center is supported in part by an NCI Cancer Center support grant P30 CA91842. Funding Information: DK is a past scholar of the German Academic Exchange Service (postdoctoral fellowship ID: 57054578, 2014–2016). MPR is supported by the National Institutes of Health, National Cancer Institute (R50 CA211466), an Alvin J. Siteman Cancer Center, Siteman Investment Program award that is supported by The Foundation for Barnes-Jewish Hospital Cancer Frontier Fund, the Barnard Trust, and a National Cancer Institute Cancer Center support grant (P30 CA091842). HC was supported by the American Society of Hematology and the Edward P. Evans Foundation. HB is a member of LOEWE Cell and Gene Therapy Frankfurt faculty, funded by the Hessian Ministry of Higher Education, Research and the Arts (III L 4-518/17.004, 2010–2018). JFD is supported by grants from the National Institutes of Health, National Cancer Institute (U54 CA199092, R01 CA152329, and R35 CA210084). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Genome Technology Access Center is partially supported by NCI Cancer Center support grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Siteman Flow Cytometry Core. The Siteman Cancer Center is supported in part by an NCI Cancer Center support grant P30 CA91842. Funding Information: Authorship note: DK and MR contributed equally to this work. Conflict of interest: DK and JFD have a patent application (PCT/US2017/059770, compositions comprising integrin inhibitors and agents that interact with a chemokine receptor). PGR, MJM, RFH, MPR, and JFD have pending patent applications (PCT/US2017/059777, integrin inhibitors and chemokine receptor agents; PCT/ US2017/059733, integrin antagonists) and report royalties received from the patent applications during the conduct of the study. PGR, MJM, RFH, MPR, DWG, and JFD have one or more additional patents listed in an appendix in the supplement. JFD has a first-tier potential conflict due to equity ownership in Magenta Therapeutics Inc. and WUGEN Inc. JFD is founder and advisor for Magenta Therapeutics Inc. and WUGEN Inc. He receives income from RiverVest Venture Partners and Magenta Therapeutics Inc.; he receives research funding from Amphivena Therapeutics, NeoimmuneTech Inc., Mac-rogenics Inc., Incyte Corp., BiolineRx, Altiris, and WUGEN Inc.; he is an Advisory Board Member for Cellworks Group, RiverVest Venture Partners, and Arch Oncology. DMM is an employee of and owns equity in Magenta Therapeutics Inc. PGR has stock in Pfizer Inc. PGR and DWG are cofounders of, consultants for, and own equity in Indalo Therapeutics, a company pursuing clinical development of RGD-binding integrin antagonists, but not of antagonists of a α4β1 (VLA4). MPR serves as a consultant for RiverVest Venture Partners, and has received research funding from Amphivena Therapeutics, Novimmmune, and Cantex. MJM receives research funding from Ultragenyx Pharmaceutical Inc. and is the founder and owner of Meyers MedChem Consulting LLC. RFH is currently an employee of Confluence Discovery Technologies. LE has received research funding from MaxCyte Inc. HBB is a coinventor of patent PCT/EP2015/066083 from which he receives royalties and licensing fees; he has received honoraria from Miltenyi, Celgene, Sandoz-Hexal, Novartis, and Terumo BCT; he has received research support from Sandoz-Hexal, Amgen, Polyphor, Stage (now Juno), Miltenyi, Terumo BCT; and he has served on the advisory boards of Genzyme, Novartis, Celgene, and Terumo BCT. Copyright: © 2019, American Society for Clinical Investigation. Submitted: September 6, 2018; Accepted: April 25, 2019; Published: June 10, 2019. Reference information: J Clin Invest. 2019;129(7): 2745–2759. https://doi.org/10.1172/JCI124738. Publisher Copyright: © 2019, American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future.
AB - Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future.
UR - http://www.scopus.com/inward/record.url?scp=85066250809&partnerID=8YFLogxK
U2 - 10.1172/JCI124738
DO - 10.1172/JCI124738
M3 - Article
C2 - 31085833
AN - SCOPUS:85066250809
SN - 0021-9738
VL - 129
SP - 2745
EP - 2759
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -