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A Three-Dimensional in Vitro Model of Erythropoiesis Recapitulates Erythroid Failure in Myelodysplastic Syndromes

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A Three-Dimensional in Vitro Model of Erythropoiesis Recapitulates Erythroid Failure in Myelodysplastic Syndromes Leukemia (2020) 34:271–282 https://doi.org/10.1038/s41375-019-0532-7 ARTICLE Myelodysplastic syndrome A three-dimensional in vitro model of erythropoiesis recapitulates erythroid failure in myelodysplastic syndromes 1 1 1 1 Edda María Elvarsdóttir ● Teresa Mortera-Blanco ● Marios Dimitriou ● Thibault Bouderlique ● 1 1 1 1 2 1 Monika Jansson ● Isabel Juliana F. Hofman ● Simona Conte ● Mohsen Karimi ● Birgitta Sander ● Iyadh Douagi ● 1 1 Petter S. Woll ● Eva Hellström-Lindberg Received: 19 January 2019 / Revised: 13 May 2019 / Accepted: 20 May 2019 / Published online: 2 August 2019 © The Author(s) 2019. This article is published with open access Abstract Established cell culture systems have failed to accurately recapitulate key features of terminal erythroid maturation, hampering our ability to in vitro model and treat diseases with impaired erythropoiesis such as myelodysplastic syndromes with ring sideroblasts (MDS-RS). We developed an efficient and robust three-dimensional (3D) scaffold culture model supporting terminal erythroid differentiation from both mononuclear (MNC) or CD34+-enriched primary bone marrow cells from healthy donors and MDS-RS patients. While CD34+ cells did not proliferate beyond two weeks in 2D suspension + 1234567890();,: 1234567890();,: cultures, the 3D scaffolds supported CD34 and MNC erythroid proliferation over four weeks demonstrating the importance of the 3D environment. CD34+ cells cultured in 3D facilitated the highest expansion and maturation of erythroid cells, including generation of erythroblastic islands and enucleated erythrocytes, while MNCs supported multi-lineage hemopoietic differentiation and cytokine secretion relevant for MDS-RS. Importantly, MDS-RS 3D-cultures supported de novo generation of ring sideroblasts and maintenance of the mutated clone. The 3D cultures effectively model a clonal disease characterized by terminal erythroid failure and can be used to assess therapeutic compounds. Introduction for this process [3–5]. It has been a challenge to establish in vitro models that fully recapitulate terminal erythropoi- Terminal erythroid differentiation involves a series of esis, limiting the elucidation of regulatory mechanisms morphologically distinct maturation stages of erythroblasts involved during healthy and defective erythropoiesis, an that following terminal enucleation are released as reticu- important prerequisite for identifying novel therapy targets locytes from the bone marrow (BM) into the blood stream for patients with anemia. where they mature into erythrocytes [1, 2]. The formation of Myelodysplastic syndromes (MDS) are hematopoietic erythroblastic islands, i.e., erythroblasts surrounding a malignancies frequently leading to severe anemia and macrophage that phagocytoses the extruded nuclei while chronic dependency on red blood cell transfusions [6]. providing nutrients and iron for heme synthesis, is critical We have focused our research on the subgroup MDS with ring sideroblasts (MDS-RS), characterized by ineffective terminal erythroid differentiation, recurrent somatic Supplementary information The online version of this article (https:// mutations in splicing factor 3b subunit 1 (SF3B1)[7–9] doi.org/10.1038/s41375-019-0532-7) contains supplementary and accumulation of aberrant mitochondrial ferritin in material, which is available to authorized users. erythroblasts, resulting in the generation of ring side- * Eva Hellström-Lindberg roblasts (RS) constituting 15–50% of nucleated erythroid [email protected] bone marrow (BM) cells [10–14]. Using suspension cul- tures, we have recapitulated healthy and MDS-RS ery- 1 Center for Hematology and Regenerative Medicine, Karolinska thropoiesis up to the stage of intermediate erythroblasts, Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden with increased mitochondrial ferritin and mitochondria- 2 mediated apoptosis [11, 15, 16]. However, to further Division of Pathology, Department of Laboratory Medicine, SF3B1 Karolinska Institutet, Karolinska University Hospital Huddinge, elucidate biological consequences of mutations for Stockholm, Sweden terminal erythropoiesis would require efficient in vitro 272 EM Elvarsdóttir et al. generation of RS and enucleated erythrocytes from MDS- culture period. While the 3D CD34+ culture mainly facili- RS stem and progenitor cells. tated erythroid maturation, the corresponding MNC cultures Our group has previously generated human RS following supported a more variable hematopoietic differentiation, xeno-transplantation of purified hematopoietic stem cells both for healthy and MDS-RS samples. All 3D cultures (HSC) into immune-compromised mice, demonstrating that supported formation of erythroblastic islands and enuclea- human HSCs are the initiating cells of the MDS-RS phe- tion and importantly MDS-RS erythropoiesis with main- notype and able to differentiate within the mouse BM [17]. tained SF3B1 mutated allele burden and development of In addition, formation of human RS was recently reported in key dysplastic features of terminal maturation. Our results an MDS patient-derived xenotransplantation model using show that the 3D scaffold system can be used to model cytokine-humanized immunodeficient mice lacking the erythroid differentiation from healthy and MDS progenitors, corresponding murine cytokines [18]. While the xenograft and indicates its usefulness for other disorders with defec- models could be a valuable in vivo platform for studying tive erythroid maturation and for assessment of therapeutic dysregulated erythroid development in MDS-RS, low compounds aiming to improve erythroid output. engraftment and recovery of MDS-RS erythroid cells from the mice limit possible experimental outputs [19, 20]. Fur- thermore, genetic mouse models allowing conditional Materials and methods expression of mutant SF3B1 have failed to generate RS, reflecting that downstream effects of mutations may differ Sample collection and culture conditions between mice and man [21, 22]. Based on the above-described limitations we set out to BM aspirates were obtained from eight healthy donors develop an in vitro three-dimensional (3D) system allowing (NBM) and eleven patients with MDS-RS, according to the for longitudinal studies of maturing erythroid cells, parti- World Health Organization 2016 revision of the classifica- cularly focused on the formation of erythroblastic islands tion of myeloid neoplasms and acute leukemia [10]. Patients and enucleated erythrocytes. As the goal was to study were diagnosed using a multi-professional conference human disease with erythroid failure we cultured primary approach. Healthy controls and patients sampled at the cells from healthy individuals (normal bone marrow; NBM) Hematology Department at Karolinska University Hospital, and patients with MDS-RS, a disease with an easily quan- Sweden, provided informed consent and the study was tifiable phenotype. Modeling the whole process of MDS-RS approved by the Ethics Research Committee at Karolinska erythropoiesis requires, in addition to RS formation, main- Institutet (2010/427-31/1 and 2011/1257-31/1). All MDS- tenance of the SF3B1 mutated clone throughout differ- RS patients were SF3B1 mutated and had non-transfusion entiation, similar to what we demonstrated in freshly dependent anemia (Supplementary Table 1). aspirated BM from MDS-RS patients [11]. For this purpose BM MNCs were isolated using Lymphoprep (Nycomed, we modified a previously described system using collagen Oslo, Norway) density gradient centrifugation. To assess coated polyurethane scaffolds with a pore size and dis- the effect of a richer cellular variety both the layered MNCs tribution of similar architecture to human BM for erythroid and the Lymphoprep fraction were harvested (Fig. 1a). A growth and differentiation [23, 24]. We compared seeding fraction of the MNCs were enriched for CD34+ cells using freshly isolated CD34+ enriched cells, a source that has magnetic-activated cell sorting (MACS; Miltenyi Biotec, been used to assess early and intermediate erythroid dif- Bergish Gladbach, Germany) according to manufacturer’s ferentiation in liquid cultures [15, 16, 25–27], to freshly protocol, resulting in CD34+ purity higher or equal to 75%. separated mononuclear cells (MNCs) that contain cells of MNCs were seeded either directly into 24-well tissue cul- multiple hematopoietic lineages, including mesenchymal ture plates (2D MNC) or into sterile scaffolds (3D MNC) stromal cells. In order to assess the effect of the 3D scaffold placed in 24-tissue culture plates at a concentration of system per se, we cultured the same cells in suspension (2D) 2×106 cells/0.1 ml medium and incubated for 15 minutes at with the same medium. To facilitate erythropoiesis we 37 °C and 5% CO2 before adding 1.4 ml of medium into based the medium composition on two weeks of erythro- each well. In order to compare the growth of BM MNCs vs. blast media, previously used to facilitate growth of ery- CD34+ in the 3D system we ensured that an equivalent throid progenitors in liquid culture [15, 16, 26], followed by number of CD34+ cells were seeded in both types of two weeks of simplified medium with iron supplementation scaffolds. For each sample we calculated the percentage of to facilitate erythroid maturation [28, 29]. CD34+ cells in the MNCs used for enrichment and seeded a We demonstrated that while primary CD34+ cells could number of CD34+ cells corresponding to 2 × 106 MNCs only be maintained for two weeks in suspension culture,
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