Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses
Jennifer Bordenave, Dorota Gajda, David Michonneau, Nicolas Vallet, Mathieu Chevalier, Emmanuelle Clappier, Pierre Lemaire, Stéphanie Mathis, Marie Robin, Aliénor Xhaard, Flore Sicre de Fontbrune, Aurélien Corneau, Sophie Caillat-Zucman, Regis Peffault de Latour, Emmanuel Curis, Gérard Socié
Jennifer Bordenave, Dorota Gajda, David Michonneau, Nicolas Vallet, Mathieu Chevalier, Emmanuelle Clappier, Pierre Lemaire, Stéphanie Mathis, Marie Robin, Aliénor Xhaard, Flore Sicre de Fontbrune, Aurélien Corneau, Sophie Caillat-Zucman, Regis Peffault de Latour, Emmanuel Curis, Gérard Socié
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Clinical Research and Public Health Hematology Immunology

Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses

Abstract

BACKGROUND Donor cell engraftment is a prerequisite of successful allogeneic hematopoietic stem cell transplantation. Based on peripheral blood analyses, it is characterized by early myeloid recovery and T and B cell lymphopenia. However, cellular networks associated with bone marrow engraftment of allogeneic human cells have been poorly described.METHODS Mass cytometry and CITE-Seq analyses were performed on bone marrow cells 3 months after transplantation in patients with acute myelogenous leukemia.RESULTS Mass cytometric analyses in 26 patients and 20 healthy controls disclosed profound alterations in myeloid and B cell progenitors, with a shift toward terminal myeloid differentiation and decreased B cell progenitors. Unsupervised analysis separated recipients into 2 groups, one of them being driven by previous graft-versus-host disease (R2 patients). We then used single-cell CITE-Seq to decipher engraftment, which resolved 36 clusters, encompassing all bone marrow cellular components. Hematopoiesis in transplant recipients was sustained by committed myeloid and erythroid progenitors in a setting of monocyte-, NK cell–, and T cell–mediated inflammation. Gene expression revealed major pathways in transplant recipients, namely, TNF-α signaling via NF-κB and the IFN-γ response. The hallmark of allograft rejection was consistently found in clusters from transplant recipients, especially in R2 recipients.CONCLUSION Bone marrow cell engraftment of allogeneic donor cells is characterized by a state of emergency hematopoiesis in the setting of an allogeneic response driving inflammation.FUNDING This study was supported by the French National Cancer Institute (Institut National du Cancer; PLBIO19-239) and by an unrestricted research grant by Alexion Pharmaceuticals.

Authors

Jennifer Bordenave, Dorota Gajda, David Michonneau, Nicolas Vallet, Mathieu Chevalier, Emmanuelle Clappier, Pierre Lemaire, Stéphanie Mathis, Marie Robin, Aliénor Xhaard, Flore Sicre de Fontbrune, Aurélien Corneau, Sophie Caillat-Zucman, Regis Peffault de Latour, Emmanuel Curis, Gérard Socié

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Figure 6

Gene expression of selected genes.

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Gene expression of selected genes. (A) Expression of selected mRNAs high...
(A) Expression of selected mRNAs highlighted on the UMAP from Figure 5A. Expression of several mRNAs expressed by myeloid-committed progenitors. (B) Functional enrichment analysis of annotated genes using hallmark collection. GSEA analysis based on log fold change from limma-trend analysis on scran-normalized data. The figure shows significant (Benjamini-Hochberg, adjusted P values < 5%) functional enrichment in biological states or processes analysis in committed myeloid progenitors (cluster 13). (C) RNA expression of S100A9 in the UMAP from Figure 5A. (D) RNA expression of granzyme A and perforin in the UMAP from R1 and R2 recipients. (E) Expression of selected mRNAs highlighted on the UMAP from Figure 5A. Expression of TBX21, TCF7, and TOX by T cells.