Single-cell dissection of human hematopoietic reconstitution after allogeneic hematopoietic stem cell transplantation

Abstract

Hematopoietic stem cell transplantation is an effective regenerative therapy for many malignant, inherited, or autoimmune diseases. However, our understanding of reconstituted hematopoiesis in transplant patients remains limited. Here, we uncover the reconstitution dynamics of human allogeneic hematopoietic stem and progenitor cells (HSPCs) at single-cell resolution after transplantation. Transplanted HSPCs underwent rapid and measurable changes during the first 30 days after transplantation, characterized by a strong proliferative response on the first day. Transcriptomic analysis of HSPCs enabled us to observe that immunoregulatory neutrophil progenitors expressing high levels of the S100A gene family were enriched in granulocyte colony-stimulating factor–mobilized peripheral blood stem cells. Transplant recipients who developed acute graft-versus-host disease (aGVHD) infused fewer S100A high immunoregulatory neutrophil progenitors, immunophenotyped as Lin - CD34 + CD66b + CD177 + , than those who did not develop aGVHD. Therefore, our study provides insights into the regenerative process of transplanted HSPCs in human patients and identifies a potential criterion for identifying patients at high risk for developing aGVHD early after transplant.

Cross-species transcriptomics reveals bifurcation point during the arterial-to-hemogenic transition

“…1f ). To investigate the hematopoietic potential of C9 and C10, we utilized marker gene sets identified from the DEGs inference method on publically available hematopoietic progenitor cell (HPC) transcriptome profiles 51 (“Methods”; Supplementary Fig. 5b ).…”

“…For the 10× Genomics droplet-based scRNA-seq dataset from Huo et al 51 , the gene expression matrix was downloaded from GEO under the accession number GSE224714. Only cells sampled from healthy controls were retained for further analysis.…”

“…3d , shadow in blue) of GJA5 + AECs was used for differential expression analysis. For the marker genes modules of HSC/MPP and LMPP from Huo et al 51 , DEGs between HSC/MPP or LMPP and all other cells are calculated. The top 20 upregulated DEGs that ranked by fold change were used for subsequent module score calculation.…”

“…The scRNA-seq data is existing data available in GEO under accession numbers: (Zhou et al 37 , GSE135202), (Baron et al 38 , GSE112642), (Zhu et al 18 , GSE137117), (Hou et al 16 , GSE139389), (Zeng et al 19 , GSE135202), (Crosse et al 27 , GSE151877), (Calvanese et al 20 , GSE162950), (La Manno et al 24 , GSE76381), (Huo et al 51 , GSE224714). Details are listed in Supplementary Data .…”

Single-cell genomics-based immune and disease monitoring in blood malignancies

“…who performed scRNA-seq on serially collected bone marrow and peripheral blood samples of 10 patients undergoing transplant for aplastic anemia. 63 By sequencing FACS-sorted CD34 + cells, they documented a proliferative burst of hematopoietic stem cells with skewing towards megakaryocyte-erythroid progenitors, in the first week after graft infusion, followed by a gradual normalization of transcriptional states to a physiologic output of progenitor differentiation until day 30, that was similar across all 10 study subjects. In contrast, scRNA-seq of unsorted populations demonstrated the heterogeneity of circulating immune cell reconstitution following day 30, with large differences in the ratios of monocytes, B and T cells.…”