Acquired nonpermissive BM microenvironment impairs HSC proliferation and maintenance, and B-cell development after HSCT

Blood Advances, vol. 10, pp. 2786–2800

Abstract

ABSTRACT: Defects in B-cell reconstitution upon hematopoietic stem cell (HSC) transplant (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective, and complete B-cell deficiency in the context of full donor chimerism in a patient with X-linked lymphoproliferative disease, and aimed to identify the contribution of the BM microenvironment in disrupted B-cell reconstitution after HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the BM of the index patient, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy HSCs, which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients' MSCs, and a progressive loss of CXCL12 expression. Indeed, survival of the patients' HSCs improved upon supplementing the in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent nonpermissive state for normal B-cell development.

Authors 16

1. Melanie de Gier Aachen 1Laboratory for Pediatric Immunology Department of Pediatrics, Leiden University Medical Center

   Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

   Affiliation as printed

   1Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

2. Jakov Korzhenevich

   Medical University of Vienna

   Affiliation as printed

   2Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

3. Franziska Schmidt

   Medical University of Vienna

   Affiliation as printed

   2Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

4. Iga Janowska

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   3Department of Rheumatology and Clinical Immunology, Freiburg University Medical Center, University of Freiburg, Freiburg, Germany

5. Monique M. van Ostaijen-ten Dam Aachen 1Laboratory for Pediatric Immunology Department of Pediatrics, Leiden University Medical Center

   Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

   Affiliation as printed

   1Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

6. Ingrid Pico‐Knijnenburg Aachen 1Laboratory for Pediatric Immunology Department of Pediatrics, Leiden University Medical Center

   Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

   Affiliation as printed

   1Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

7. Davy Cats Aachen 4Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   4Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands

8. Petra Hadlová

   Charles University

   Affiliation as printed

   5Childhood Leukaemia Investigation Prague-Cytometry, Department of Paediatric Hematology and Oncology, 2nd Medical School, Charles University, Prague 5, Czech Republic

9. Mirjam Kunze

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   6Department of Obstetrics and Gynecology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

10. Filiz Markfeld-Erol

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    6Department of Obstetrics and Gynecology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

11. Kilian Reising

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    7Department of Orthopedic Surgery and Traumatology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

12. Hailiang Mei Aachen 4Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    4Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands

13. Robbert G. M. Bredius Aachen 8Pediatric Stem Cell Transplantation Unit Department of Pediatrics, Leiden University Medical Center

    Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

    Affiliation as printed

    8Pediatric Stem Cell Transplantation Unit, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

14. Arjan C. Lankester Aachen 8Pediatric Stem Cell Transplantation Unit Department of Pediatrics, Leiden University Medical Center

    Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

    Affiliation as printed

    8Pediatric Stem Cell Transplantation Unit, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

15. Mirjam van der Burg corresponding Aachen 1Laboratory for Pediatric Immunology Department of Pediatrics, Leiden University Medical Center

    Leiden University Medical Center · Willem-Alexander Kinderziekenhuis

    Affiliation as printed

    1Laboratory for Pediatric Immunology, Department of Pediatrics, Leiden University Medical Center, Willem Alexander Children’s Hospital, Leiden, The Netherlands

16. Marta Rizzi

    University of Freiburg · University Medical Center Freiburg · Medical University of Vienna

    Affiliation as printed

    10Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany

    2Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria

    3Department of Rheumatology and Clinical Immunology, Freiburg University Medical Center, University of Freiburg, Freiburg, Germany

    9Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany