Single-Cell RNA Sequencing Identifies Phenotypically, Functionally, and Anatomically Distinct Stromal Niche Populations in Human Bone Marrow

Li, Hongzhe; Bräunig, Sandro; Dhapola, Parashar; Karlsson, Göran; Lang, Stefan; Scheding, Stefan

doi:10.1182/blood-2022-167740

Cited by 4 publications

(3 citation statements)

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“…In this study, while systematically include ex vivo all these different cell subsets in culture, we used specific multi-color flow cytometry panel to focus on elucidation of the relative survival of PCs, B and T cells at different timepoints. Future studies may be supplemented by more in-depth analysis of the cellular composition of our BM model with advanced single cell analysis technologies, such as CITE-seq/scRNA-seq [44,45] which may provide insights into whether the loss of specific (rarer) cell subsets precede PCs decay in our system. Such results would be instrumental to propose hypothesis-driven changes to optimize medium compositions to extend PCs survival or change the composition of the hydrogel, to modulate stiffness and pore sizes.…”

Section: Discussionmentioning

confidence: 99%

Long-term in vitro maintenance of plasma cells in a hydrogel-enclosed human bone marrow microphysiological 3D model system

Martini,

Drzeniek,

Stark

et al. 2024

Biofabrication

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Plasma cells (PCs) in bone marrow (BM) play an important role in both protective and pathogenic humoral immune responses, e.g., in various malignant and non-malignant diseases such as multiple myeloma (MM), primary and secondary immunodeficiencies and autoimmune diseases. Dedicated microenvironmental niches in the BM provide PCs with biomechanical and soluble factors that support their long-term survival. There is a high need for appropriate and robust model systems to better understand PCs biology, to develop new therapeutic strategies for PCs-related diseases and perform targeted preclinical studies with high predictive value. Most preclinical data have been derived from in vivo studies in mice, as in vitro studies of human PCs are limited due to restricted survival and functionality in conventional 2D cultures that do not reflect the unique niche architecture of the BM. We have developed a microphysiological, dynamic 3D BM culture system (BM-MPS) based on human primary tissue (femoral biopsies), mechanically supported by a hydrogel scaffold casing. While a bioinert agarose casing did not support PCs survival, a photo-crosslinked collagen-hyaluronic acid (Col-HA) hydrogel preserved the native BM niche architecture and allowed PCs survival in vitro for up to 2 weeks. Further, the Col-HA hydrogel was permissive to lymphocyte migration into the microphysiological system´s circulation. Long-term PCs survival was related to the stable presence in the culture of soluble factors, as APRIL, BAFF, and IL-6. Increasing immunoglobulins concentrations in the medium confirm their functionality over culture time. To the best of our knowledge, this study is the first report of successful long-term maintenance of primary-derived non-malignant PCs in vitro. Our innovative model system is suitable for in-depth in vitro studies of human PCs regulation and exploration of targeted therapeutic approaches such as CAR-T cell therapy or biologics.

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Section: Discussionmentioning

confidence: 99%

Long-term in vitro maintenance of plasma cells in a hydrogel-enclosed human bone marrow microphysiological 3D model system

Martini,

Drzeniek,

Stark

et al. 2024

Biofabrication

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“…We further obtained scRNA-seq data of BM stromal cells from Li et al 41 for investigating the mechanisms of HSPCs migration out of BM. The scRNA-seq of thymic stromal cells were obtained from Bautista et al 42 for investigating the HSPCs seeding to thymus.…”

Section: Methodsmentioning

confidence: 99%

Differentiation and migration of hematopoietic stem and progenitor cells cross multiple tissues

Yu,

Li,

Wang

et al. 2023

Preprint

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Hematopoiesis requires the coordinated differentiation of hematopoietic stem cells and progenitor cells (HSPCs) in multiple tissues. Although differentiation of HSPCs in bone marrow (BM) has been well-studied, our knowledge about the migration and differentiation of HSPCs cross tissues is limited. Here, we collected and integrated single-cell RNA-seq data of human CD34+ cells, which represent HSPCs, from BM, peripheral blood (PB), thymus and mobilized PB (mPB), to investigate the hematopoiesis cross tissues. We constructed a cell atlas of HSPCs cross tissues and found most HSPC subsets in BM had counterparts in PB, indicating migration of HSPCs from BM to PB has a much broad spectrum. We found B progenitors highly expressed CXCR4 for anchoring in BM, while cells with low expression of CXCR4 facilitate their migration out of BM. Among the HSPC subsets from thymus, we only found the counterparts of the earliest thymic progenitors (ETPs) in BM and PB, potentially indicating that ETPs were the subsets that migrated from BM to PB and thymus. We found interaction signaling including CD99-CD99, CXCL12-CXCR4 and CCL19-CCR7 played important roles in ETP homing to thymus. Briefly, these data provided a single unified developmental spectrum of hematopoiesis cross different tissues, connected by cell migration.

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“…Similarly, Buechler et al (2021) illustrated the compartmentalisation of the murine fibroblast lineage into universal, specialised and activated subtypes, whereby a universal/common ancestor fibroblast population gives rise to tissue‐specific specialised subtypes (steady state) that may acquire an activated phenotype during disease/infection. Based on these studies, scRNA‐seq of human bone marrow stroma (CD45 low/− CD235a − CD271 + ) identified six stromal cell types across nine clusters, which included pre‐fibroblasts and multipotent stromal stem cells (Li et al, 2022).…”

Section: Characterisation Of Distinct Fibroblast and Mesenchymal Stem...mentioning

confidence: 99%

Stromal bone marrow fibroblasts and mesenchymal stem cells support acute myeloid leukaemia cells and promote therapy resistance

Miari

Williams

2023

British J Pharmacology

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The bone marrow (BM) is the primary site of adult haematopoiesis, where stromal elements (e.g. fibroblasts and mesenchymal stem cells [MSCs]) work in concert to support blood cell development. However, the establishment of an abnormal clone can lead to a blood malignancy, such as acute myeloid leukaemia (AML). Despite our increased understanding of the pathophysiology of the disease, patient survival remains suboptimal, mainly driven by the development of therapy resistance. In this review, we highlight the importance of bone marrow fibroblasts and MSCs in health and acute myeloid leukaemia and their impact on patient prognosis. We discuss how stromal elements reduce the killing effects of therapies via a combination of contactdependent (e.g. integrins) and contact-independent (i.e. secreted factors) mechanisms, accompanied by the establishment of an immunosuppressive microenvironment. Importantly, we underline the challenges of therapeutically targeting the bone marrow stroma to improve acute myeloid leukaemia patient outcomes, due to the inherent heterogeneity of stromal cell populations.

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Single-Cell RNA Sequencing Identifies Phenotypically, Functionally, and Anatomically Distinct Stromal Niche Populations in Human Bone Marrow

Cited by 4 publications

References 0 publications

Long-term in vitro maintenance of plasma cells in a hydrogel-enclosed human bone marrow microphysiological 3D model system

Long-term in vitro maintenance of plasma cells in a hydrogel-enclosed human bone marrow microphysiological 3D model system

Differentiation and migration of hematopoietic stem and progenitor cells cross multiple tissues

Stromal bone marrow fibroblasts and mesenchymal stem cells support acute myeloid leukaemia cells and promote therapy resistance

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