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Ectopic humanized mesenchymal niche in mice enables robust engraftment of myelodysplastic stem cells.

ABSTRACT: Myelodysplastic syndrome (MDS) are clonal stem cell diseases characterized mainly by ineffective hematopoiesis. Here, we present an approach that enables robust long-term engraftment of primary MDS stem cells (MDS-SCs) in mice by implantation of human mesenchymal cell-seeded scaffolds. Critically for modelling MDS, where patient sample material is limiting, mononuclear bone marrow cells containing as few as 10⁴ CD34⁺ cells can be engrafted and expanded by this approach with the maintenance of the genetic make-up seen in the patients. Non-invasive high-resolution ultrasound imaging shows that these scaffolds are fully perfused. Our data shows that human microenvironment but not mouse is essential to MDS-SCs homing and engraftment. Notably, the alternative niche provided by healthy donor MSCs enhanced engraftment of MDS-SCs. This study characterizes a new tool to model MDS human disease with the level of engraftment previously unattainable in mice, and offers insights into human-specific determinants of MDS-SC microenvironment.

SUBMITTER: Mian SA

PROVIDER: S-EPMC7610449 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Ectopic humanized mesenchymal niche in mice enables robust engraftment of myelodysplastic stem cells.

Mian Syed A SA Abarrategi Ander A Kong Kar Lok KL Rouault-Pierre Kevin K Wood Henry H Oedekoven Caroline A CA Smith Alexander E AE Batsivari Antoniana A Ariza-McNaughton Linda L Johnson Peter P Snoeks Thomas T Mufti Ghulam J GJ Bonnet Dominique D

Blood cancer discovery 20201223 2

Myelodysplastic syndrome (MDS) are clonal stem cell diseases characterized mainly by ineffective hematopoiesis. Here, we present an approach that enables robust long-term engraftment of primary MDS stem cells (MDS-SCs) in mice by implantation of human mesenchymal cell-seeded scaffolds. Critically for modelling MDS, where patient sample material is limiting, mononuclear bone marrow cells containing as few as 10<sup>4</sup> CD34<sup>+</sup> cells can be engrafted and expanded by this approach with ...[more]

PMID: 33778768

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Project description:BackgroundCell-based therapy holds great promises for demyelinating diseases. Human-derived fetal and adult oligodendrocyte progenitors (OPC) gave encouraging results in experimental models of dysmyelination but their limited proliferation in vitro and their potential immunogenicity might restrict their use in clinical applications. Virtually unlimited numbers of oligodendroglial cells could be generated from long-term self-renewing human (h)-derived neural stem cells (hNSC). However, robust oligodendrocyte production from hNSC has not been reported so far, indicating the need for improved understanding of the molecular and environmental signals controlling hNSC progression through the oligodendroglial lineage. The aim of this work was to obtain enriched and renewable cultures of hNSC-derived oligodendroglial cells by means of epigenetic manipulation.Methodology/principal findingsWe report here the generation of large numbers of hNSC-derived oligodendroglial cells by concurrent/sequential in vitro exposure to combinations of growth factors (FGF2, PDGF-AA), neurotrophins (NT3) and hormones (T3). In particular, the combination FGF2+NT3+PDGF-AA resulted in the maintenance and enrichment of an oligodendroglial cell population displaying immature phenotype (i.e., proliferation capacity and expression of PDGFRalpha, Olig1 and Sox10), limited self-renewal and increased migratory activity in vitro. These cells generate large numbers of oligodendroglial progeny at the early stages of maturation, both in vitro and after transplantation in models of CNS demyelination.Conclusions/significanceWe describe a reliable method to generate large numbers of oligodendrocytes from a renewable source of somatic, non-immortalized NSC from the human foetal brain. We also provide insights on the mechanisms underlying the pro-oligodendrogenic effect of the treatments in vitro and discuss potential issues responsible for the limited myelinating capacity shown by hNSC-derived oligodendrocytes in vivo.

Dataset Information

Ectopic humanized mesenchymal niche in mice enables robust engraftment of myelodysplastic stem cells.

Publications

Ectopic humanized mesenchymal niche in mice enables robust engraftment of myelodysplastic stem cells.

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