cMPL-based purification and depletion of human hematopoietic stem cells: implications for pretransplant conditioning
Abstract
Abstract The thrombopoietin:cMPL signaling axis is a critical regulator of early hematopoiesis. However, the utility of cMPL as a standalone marker for identifying long-term repopulating hematopoietic stem cells (LT-HSCs) within the adult human CD34+ hematopoietic stem and progenitor cell (HSPC) population has not been validated. In this study, we established high cMPL surface expression as a defining feature of human LT-HSCs. Targeting the cMPL receptor facilitated the separation of human LT-HSCs from mature progenitors, a delineation not achievable with c-KIT (CD117). Leveraging this finding, we explored the therapeutic potential of cMPL as a novel target for pretransplant conditioning regimens. We developed a cMPL-targeting immunotoxin and demonstrated its ability to preferentially deplete host cMPLhigh LT-HSCs in murine xenograft models. Evaluation in rhesus macaques confirmed these findings and highlighted a favorable safety profile with rapid systemic clearance within 24 hours of administration. Proof of concept experiments validated the immunotoxin as a novel conditioning agent, enabling donor HSPC engraftment without the use of chemotherapy or irradiation. These findings advance our understanding of the molecular determinants of human hematopoiesis and underscore the potential of cMPL-targeting preparative regimens to improve therapeutic transplantation outcomes.
Article Details
Authors (15)
Daisuke Araki
1Laboratory of Regenerative Therapies for Inherited Blood Disorders, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United States
So Gun Hong
1Translational Stem Cell Biology Branch, NIH/NHLBI, Bethesda, United States
Nathaniel Linde
1Translational Stem Cell Biology Branch, NIH/NHLBI, Bethesda, United States
Bryan Fisk
3Integrated Data Science Services, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Neelam Redekar
Christi Salisbury-Ruf
1Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Allen Krouse
3Integrated Data Science Services, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Theresa Engels
1Translational Stem Cell Biology Branch, NIH/NHLBI, Bethesda, United States
Justin Golomb
1Translational Stem Cell Biology Branch, NIH/NHLBI, Bethesda, United States
Pradeep Dagur
5Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Sumith R. Panicker
6Laboratory of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Yogendra Kanthi
6Laboratory of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Diogo M. Magnani
Zhirui Wang
Andre Larochelle
1Laboratory of Regenerative Therapies for Inherited Blood Disorders, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United States