Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Khan, Abdullah O.; Colombo, M.; Reyat, Jasmeet S.; Wang, Guanlin; Rodriguez-Romera, Antonio; Wen, Wei; Murphy, Lauren C.; Grygielska, Beata; Mahony, Christopher B.; Stone, Abraham; Croft, Adam P.; Bassett, D. C.; Pooligasundarampillai, Gowsihan; Roy, Anindita; Gooding, Sarah; Rayes, Julie; Machlus, Kellie R.; Psaila, Bethan

doi:10.1101/2022.03.14.483815

Cited by 5 publications

(5 citation statements)

References 69 publications

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“…Several recent reports have demonstrated the utility of organ-on-a-chip (Ooc) solutions for the recreation of adult bone marrow environments in physiological (Sugimura et al, 2020; Torisawa et al, 2014) and pathological (Abdullah Obaid Khan et al, 2022; Chou et al, 2020), i.e. leukemia settings.…”

Section: Discussionmentioning

confidence: 99%

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Ragusa

Suen

Cortes

et al. 2022

Preprint

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Current in vitro models of developmental blood formation lack spatiotemporal coherence and weakly replicate the hematopoietic microenvironment. Developmentally-appropriate models can enhance understanding of infant acute myeloid leukemia (infAML), which putatively originates in utero and has 50% age-unique genetic events, suggesting unique biology. The commonest genetic abnormality unique to infants involves homeobox gene MNX1, whose leukemogenic mechanisms remain unknown. Recently, 3D self-organising embryonic stem cell (SC)-based gastruloids have shown promise in recapitulating embryonic events with time/space precision. Herein, we report a hemogenic gastruloid (haemGx) system that captures multi-wave blood formation, progenitor specification from hemogenic endothelium (HE), and approximates generation of hematopoietic SC precursors. Enforced MNX1 expression in haemGx promotes HE formation, perturbs endothelial-to-hemogenic transition, and critically achieves transformation, generating myeloid colonies which display MNX1 AML signatures. By combining functional assays with single-cell transcriptomics, we establish the haemGx as a new model of normal and leukemic embryonic hematopoiesis amenable to mechanistic exploration.

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Section: Discussionmentioning

confidence: 99%

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Ragusa

Suen

Cortes

et al. 2022

Preprint

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“…In an alternative approach, induced pluripotent stem cells are initially aggregated and induced towards mesodermal aggregates, 90 modifying our initial BVO protocol. 41,42 After induction towards vascular and hematopoietic lineage through addition of BMP4, FGF2, VEGF-A, SCF (stem cell factor), and Flt3 (Fms-like tyrosine kinase 3), the organoids were embedded in a hydrogel of collagen/Matrigel mixture.…”

Section: Organotypic Vasculature and Specific Functionsmentioning

confidence: 99%

Blood Vessel Organoids for Development and Disease

Salewskij

Penninger

2023

Circulation Research

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Despite enormous advances, cardiovascular disorders are still a major threat to global health and are responsible for one-third of deaths worldwide. Research for new therapeutics and the investigation of their effects on vascular parameters is often limited by species-specific pathways and a lack of high-throughput methods. The complex 3-dimensional environment of blood vessels, intricate cellular crosstalks, and organ-specific architectures further complicate the quest for a faithful human in vitro model. The development of novel organoid models of various tissues such as brain, gut, and kidney signified a leap for the field of personalized medicine and disease research. By utilizing either embryonic- or patient-derived stem cells, different developmental and pathological mechanisms can be modeled and investigated in a controlled in vitro environment. We have recently developed self-organizing human capillary blood vessel organoids that recapitulate key processes of vasculogenesis, angiogenesis, and diabetic vasculopathy. Since then, this organoid system has been utilized as a model for other disease processes, refined, and adapted for organ specificity. In this review, we will discuss novel and alternative approaches to blood vessel engineering and explore the cellular identity of engineered blood vessels in comparison to in vivo vasculature. Future perspectives and the therapeutic potential of blood vessel organoids will be discussed.

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“…It was demonstrated that this system allows for drug screening in the context of myelofibrosis, but more importantly supports the engraftment of primary patient cells from several cancers which have been classically difficult to study ex vivo (primary myelofibrosis, multiple myeloma, acute lymphocytic leukemia). 230 …”

Section: Theme 4: Hemostasis In Extracorporeal Systems: the Value And...mentioning

confidence: 99%

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis

et al. 2023

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The 4th Maastricht Consensus Conference on Thrombosis (MCCT), included the following themes: Theme 1: The “coagulome” as a critical driver of cardiovascular disease Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infections associated-coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies This theme included state of the art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: how to utilize ex vivo models? Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularised organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation (ECMO) associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management Plenary presentations addressed controversial areas, ie thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies and clinically tested factor XI(a) inhibitors,both possibly with reduced bleeding risk. Finally, Covid-19 associated coagulopathy is revisited.

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Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

Cited by 5 publications

References 69 publications

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Dissecting infant leukemia developmental origins with a hemogenic gastruloid model

Blood Vessel Organoids for Development and Disease

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis

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