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Single-cell multiomics of human fetal hematopoiesis defines a developmental specific population and a fetal signature

ABSTRACT: Knowledge of human fetal blood development and how it differs from adult is highly relevant to our understanding of congenital blood and immune disorders and childhood leukemia, of which the latter can originate in utero. Blood formation occurs in waves that overlap in time and space adding to heterogeneity, which necessitates single-cell approaches. Here, a combined single cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (Cellular-Indexing-of-Transcriptomes-and-Epitopes-by-Sequencing) the molecular profile of established immunophenotypic gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs) such as CD90 and CD49F were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow (BM) dataset revealed that the HSC state was less frequent in FL, whereas cells with lympho-myeloid signature were more abundant. An erythro-myeloid primed multipotent progenitor cluster was identified, potentially representing a transient, fetal-specific population. Furthermore, differentially expressed genes between fetal and adult counterparts were specifically analyzed, and a fetal core signature identified. The core gene set could separate subgroups of Acute Lymphoblastic Leukemia (ALL) by age, suggesting that a fetal program may be partially retained in specific sub-groups of pediatric leukemia. Our detailed single-cell map presented herein emphasizes molecular and immunophenotypic differences between fetal and adult blood cells, of significance for future studies of pediatric leukemia and blood development in general.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192966 | GEO | 2023/06/28

REPOSITORIES: GEO

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Project description:Fetal cartilage fully regenerates following injury while in adult mammals cartilage injury leads to osteoarthritis (OA). OA is characterized by cartilage breakdown and joint inflammation and associated with significant pain and socioeconomic costs. As no clinically satisfactory treatment is available to date, disease-modifying therapies aimed to achieve cartilage regeneration are urgently required. The inherent regeneration potential of fetal individuals may hold answers to this unmet need. Therefore, to characterize the differences in fetal and adult response to cartilage injury, we carried out histology and comprehensive proteome analyses on fetal (day 80/150-day gestation) and adult cartilage samples one (fetal samples) and three (adult and fetal samples) days after surgical induction of a full-thickness cartilage lesion. In addition, proteins secreted by inflamed fetal MSCs in vitro were compared with the in vivo response to injury to evaluate their therapeutic potential. Histology of synovial samples revealed the presence of neutrophils one day post injury (p.i.) and an influx of macrophages into the subsynovial tissue on day 3 p.i. in fetal samples. In contrast, adult synovial samples showed invasion of neutrophils on day 3 p.i. Activation and migration of Iba1+- macrophages of the synovial lining was observed both in fetal and adult animals. Comparative mass spectrometry revealed 57 proteins significantly up-regulated (> 2FC, FDR<0.05), and 67 proteins significantly down-regulated (<-2 FC) upon injury in adults. Neutrophil-related proteins and acute phase proteins were the two major upregulated protein groups in adult cartilage following injury compared to fetal sheep. In contrast, several immunomodulating proteins and growth factors were significantly higher expressed in the fetus than the adult. Comparison of the in vitro MSCs with the in vivo fetal proteome revealed shared upregulation of 17 proteins, which were considered to be of potential therapeutic interest. The results of this study support our molecular understanding of successful fetal cartilage healing and new therapeutic strategies to induce regeneration in adult articular cartilage by modulating the inflammatory environment. The shared protein upregulation in fetal cartilage in vivo and in fetal MSCS during in vitro inflammation supports the possible therapeutic potential of these factors in specific and fetal MSCs in general.

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Single-cell multiomics of human fetal hematopoiesis defines a developmental specific population and a fetal signature

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