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Deciphering engraftment of bone marrow human single cells after allogeneic stem cell transplantation

ABSTRACT: Engraftment of donor cells is a prerequisite to successful allogeneic hematopoietic stem cell transplantation. However, it has been poorly characterized in detail both in experimental models and in human. Bone marrow examination by mass cytometry in 26 patients with myeloid malignancies and 20 healthy donors provides evidence that the proportions of myeloid and B-cell progenitors profoundly differed as compared to healthy controls with a shift toward terminal myeloid differentiation and sharp decrease of myeloid and B-cell progenitors. Principal component analysis clearly separated in 2 recipient groups (R1 and R2) driven by previous GVHD (in R2 patients). We then used single cell CITEseq to decipher donor cell engraftment in 10/26 patients (compared with 4 healthy donors). Forty-one clusters were resolved encompassing all bone marrow cellular components. Projection of patients and R1 and R2 showed drastic segregation of the 2 patient groups which were highly significant different repartition in a compositional analysis. In R2 patients sustained engraftment relied on only 10 clusters that included only committed myeloid progenitors, one stem-cell memory T-cell cluster and activated NK-cell clusters. Gene expression hallmarks disclosed repeatedly similar pathway in transplant recipients, namely, TNFα signaling via NFĸ, interferonƔ response, and allograft rejection. Thus, the cellular composition of the engrafted bone marrow in human is strongly influenced by T-cell mediated processes and inflammation leading to an emergency hematopoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249722 | GEO | 2024/10/01

REPOSITORIES: GEO

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Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

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Deciphering engraftment of bone marrow human single cells after allogeneic stem cell transplantation

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