Early growth response 1 regulates hematopoietic support and proliferation in human primary bone marrow stromal cells

Li, Hongzhe; Lim, Hooi-Ching; Zacharaki, Dimitra; Xian, Xiaojie; Kenswil, Keane Jared Guillaume; Bräunig, Sandro; Raaijmakers, Marc H.G.P.; Woods, Niels‐Bjarne; Hansson, Jenny; Scheding, Stefan

doi:10.3324/haematol.2019.216648

Cited by 12 publications

(10 citation statements)

References 34 publications

(43 reference statements)

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“…We therefore investigated cellular interactions based on ligand-receptor interactions and found a broad and complicated crosstalk network, which is likely to reflect – at least in part – the in-situ situation as data were generated with directly isolated cells. We found that stromal cells generally showed hematopoiesis supporting potential, which is consistent with previously published in-vitro coculture data (Li et al, 2014; Li et al, 2020) and which we confirmed in co-cultures with BM CD34 + cells and MSSC- or OC-derived stromal feeder cells (Fig. S7E).…”

Section: Discussionsupporting

confidence: 92%

Single-cell RNA sequencing identifies phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow

Bräunig

Lang

et al. 2022

Preprint

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Hematopoiesis is regulated by the bone marrow (BM) stroma. However, cellular identities and functions of the different BM stromal elements in humans remain poorly defined. Based on single-cell RNA sequencing, we systematically characterized the BM stromal compartment which led to the identification of six transcriptionally and functionally distinct stromal cell populations. Stromal cell differentiation hierarchy was recapitulated based on RNA velocity analysis, in vitro proliferation capacities and differentiation potentials. Potential key factors that govern the transition from stem and progenitor cells to fate-committed cells were identified. Cell-cell communication and in situ localization analysis demonstrated distinct hematopoietic stromal cell niches in specific BM locations, which used either the CXCL12 or SPP1 axis as the major hematopoiesis-regulating mechanism. These findings provide the basis for a comprehensive understanding of the cellular complexity of the human BM microenvironment and the intricate stroma-hematopoiesis crosstalk mechanisms, thus refining our current view on hematopoietic niche organization.

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Section: Discussionsupporting

confidence: 92%

Single-cell RNA sequencing identifies phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow

Bräunig

Lang

et al. 2022

Preprint

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“…The majority of these regulate stem cell functions, including FOS, FOSB, HMGB3, EGR1, PPARG, ATF4, NFE2L1, and SOX4 ( Ghazanfari et al, 2017 ). Among these, EGR1 has been studied in human MSCs due to its function in regulating MSCs’ paracrine activity inducing the release of hematopoietic supportive factors ( Tamama and Barbeau, 2012 ; Li et al, 2020 ). In particular, it has been shown that human ex vivo expanded MSCs, engineered to overexpress EGR1, sustain HSPC expansion and maintenance in 2D co-culture more efficiently than control cells ( Li et al, 2020 ; Figure 3 ).…”

Section: Discussion: Challenges and Perspectives For Mesenchymal Stromal Cells In The Context Of Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

“…Among these, EGR1 has been studied in human MSCs due to its function in regulating MSCs’ paracrine activity inducing the release of hematopoietic supportive factors ( Tamama and Barbeau, 2012 ; Li et al, 2020 ). In particular, it has been shown that human ex vivo expanded MSCs, engineered to overexpress EGR1, sustain HSPC expansion and maintenance in 2D co-culture more efficiently than control cells ( Li et al, 2020 ; Figure 3 ). These results correlate with more robust engraftment of long-term repopulating HSPCs into a pre-clinical model of transplantation.…”

Section: Discussion: Challenges and Perspectives For Mesenchymal Stromal Cells In The Context Of Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome

Crippa

Santi

Berti

et al. 2021

Front. Cell Dev. Biol.

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Overall, the human organism requires the production of ∼1 trillion new blood cells per day. Such goal is achieved via hematopoiesis occurring within the bone marrow (BM) under the tight regulation of hematopoietic stem and progenitor cell (HSPC) homeostasis made by the BM microenvironment. The BM niche is defined by the close interactions of HSPCs and non-hematopoietic cells of different origin, which control the maintenance of HSPCs and orchestrate hematopoiesis in response to the body’s requirements. The activity of the BM niche is regulated by specific signaling pathways in physiological conditions and in case of stress, including the one induced by the HSPC transplantation (HSCT) procedures. HSCT is the curative option for several hematological and non-hematological diseases, despite being associated with early and late complications, mainly due to a low level of HSPC engraftment, impaired hematopoietic recovery, immune-mediated graft rejection, and graft-versus-host disease (GvHD) in case of allogenic transplant. Mesenchymal stromal cells (MSCs) are key elements of the BM niche, regulating HSPC homeostasis by direct contact and secreting several paracrine factors. In this review, we will explore the several mechanisms through which MSCs impact on the supportive activity of the BM niche and regulate HSPC homeostasis. We will further discuss how the growing understanding of such mechanisms have impacted, under a clinical point of view, on the transplantation field. In more recent years, these results have instructed the design of clinical trials to ameliorate the outcome of HSCT, especially in the allogenic setting, and when low doses of HSPCs were available for transplantation.

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“…Bone marrow (BM) mesenchymal stromal cells (MSCs) are self‐renewing, multipotent cells that can differentiate into osteocytes, adipocytes, and chondrocytes. They play important roles in maintaining the hematopoietic niche and regulate marrow immune homeostasis (1–7). MSCs have also been investigated intensively for cell therapies including regenerative medicine and immuno modulatory approaches and can be isolated from several different tissues.…”

Section: Figurementioning

confidence: 99%

“…Acoustically separated MSCs and controls, respectively, were differentiated toward the adipogenic, osteogenic, and chondrogenic lineages as described previously (5). Negative control samples were cultured in standard MSC medium (StemMACS MSC Expansion Media, human [Miltenyi Biotec, Bergisch Gladbach, Germany], supplemented with 1% antibiotic-antimycotic solution [Sigma-Aldrich]).…”

Section: In Vitro Differentiation Assaysmentioning

confidence: 99%

Acoustophoresis Enables the Label‐Free Separation of Functionally Different Subsets of Cultured Bone Marrow Stromal Cells

et al. 2020

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Culture‐expanded mesenchymal stromal cells (MSCs) are promising candidates for clinical cell‐based therapies. MSC products are heterogeneous and we therefore investigated whether acoustophoresis, an ultrasound‐based separation technology, could be used for the label‐free enrichment of functionally different MSC populations. Acoustophoresis uses an ultrasonic standing wave field in a microchannel that differentially affects the movement of cells depending on their acoustophysical properties, such as size, density, and compressibility. Human bone marrow (BM) MSCs were generated by standard adherent culture in xeno‐free medium and separated by microchip acoustophoresis. MSCs with up to 20% higher proliferation and 1.7‐fold increased clonogenic potential were enriched in the side outlet of the chip compared to the input sample. These cells were significantly smaller (average diameter 14.5 ± 0.4 μm) compared to the center outlet fraction (average diameter 17.1 ± 0.6 μm) and expressed higher levels of genes related to proliferation and stem cell properties (i.e., Ki‐67 [1.9‐fold], Nanog1 [6.65‐fold], Oct4 [2.9‐fold], and CXCL12 [1.8‐fold], n = 3) in the side outlet compared to input. Fractions of MSCs in G0/G1 cell cycle phase were significantly enriched in the side fraction and an up to 2.8‐fold increase of cells in S/G2/M phases were observed in center fractions compared to side fractions and 1.3‐fold increased compared to the input sample. Acoustophoresis did not compromise MSC phenotype, proliferation, clonogenic capacity, and viability (generally 87–98%), nor did it affect differentiation or immunomodulatory capacities. These results demonstrate that label‐free acoustic separation can enrich functionally different MSC subsets which can potentially be employed to produce better‐defined stromal cell products from cultured MSCs. Hence, acoustophoresis is a potentially promising separation technology to provide improved cell products for research and possible future clinical use. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals LLC. on behalf of International Society for Advancement of Cytometry.

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Early growth response 1 regulates hematopoietic support and proliferation in human primary bone marrow stromal cells

Cited by 12 publications

References 34 publications

Single-cell RNA sequencing identifies phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow

Single-cell RNA sequencing identifies phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow

Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome

Acoustophoresis Enables the Label‐Free Separation of Functionally Different Subsets of Cultured Bone Marrow Stromal Cells

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