Generation of complex bone marrow organoids from human induced pluripotent stem cells

Frenz-Wiessner, Stephanie; Fairley, Savannah D.; Buser, Maximilian; Goek, Isabel; Salewskij, Kirill; Jonsson, Gustav; Illig, David; zu Putlitz, Benedicta; Petersheim, Daniel; Li, Yue; Chen, Pin-Hsuan; Kalauz, Martina; Conca, Raffaele; Sterr, Michael; Geuder, Johanna; Mizoguchi, Yoko; Megens, Remco T. A.; Linder, Monika I.; Kotlarz, Daniel; Rudelius, Martina; Penninger, Josef M.; Marr, Carsten; Klein, Christoph

doi:10.1038/s41592-024-02172-2

Cited by 20 publications

(1 citation statement)

References 72 publications

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“…We initially attempted to use stem cell transplantation to track cancer and wild-type clones, but these assays were underpowered, tracking too few clones, which is possibly due to mutant cell competition or niche heterogeneity. Our defined primary stem cell culture system is powerful as a proof of principle, but future technological implementations should address the role of niches and extrinsic components, which may take advantage of organoids or co-culture systems (Sommerkamp et al 2021; Frenz-Wiessner et al 2024; Khan et al 2023).…”

Section: Discussionmentioning

confidence: 99%

Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of cancer driver mutations

Singh,

Fernandez-Perez,

Sanchez-Sanchez

et al. 2024

Preprint

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Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but these assays have traditionally relied on surface markers, lacking the clonal resolution to distinguish heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed STRACK, an unbiased framework to longitudinally trace clonal gene expression and expansion dynamics before and after acquisition of cancer mutations. We studied two different leukemia driver mutations, Dnmt3a-R882H and Npm1cA, and found that the response to both mutations was highly variable across different stem cell states. Specifically, a subset of differentiation-biased stem cells, which normally become outcompeted with time, can efficiently expand with both mutations. Npm1c mutations surprisingly reversed the intrinsic bias of the clone-of-origin, with stem-biased clones giving rise to more mature malignant states. We propose a clonal reaction norm, in which pre-existing clonal states show different cancer phenotypic potential.

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Section: Discussionmentioning

confidence: 99%

Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of cancer driver mutations

Singh,

Fernandez-Perez,

Sanchez-Sanchez

et al. 2024

Preprint

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Organoids of Musculoskeletal System for Disease Modeling, Drug Screening, and Regeneration

Chen,

Liu,

et al. 2024

Adv Healthcare Materials

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Musculoskeletal diseases have emerged as the leading cause of disability worldwide, with their prevalence increasing annually. In light of this escalating health challenge, organoids, an emerging technology in tissue engineering, offer promising solutions for disease modeling, drug screening, regeneration, and repair processes. The successful development of musculoskeletal organoids represents a significant breakthrough, providing a novel platform for studying musculoskeletal diseases and facilitating the discovery of new treatments. Moreover, organoids serve as valuable complements to traditional 2D culture methods and animal models, offering rich insights into musculoskeletal biology. This review provides an overview of organoid technology, outlining the construction processes of various musculoskeletal organoids and highlighting their similarities and differences. Furthermore, the challenges associated with organoid technology in musculoskeletal systems are discussed and insights into future perspectives are offered.

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Matrix Viscoelasticity Controls Differentiation of Human Blood Vessel Organoids into Arterioles and Promotes Neovascularization in Myocardial Infarction

Sun,

Zhang,

Zheng

et al. 2024

Advanced Materials

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Stem cell‐derived blood vessel organoids are embedded in extracellular matrices to stimulate vessel sprouting. Although vascular organoids in 3D collagen I‐Matrigel gels are currently available, they are primarily capillaries composed of endothelial cells (ECs), pericytes, and mesenchymal stem‐like cells, which necessitate mature arteriole differentiation for neovascularization. In this context, the hypothesis that matrix viscoelasticity regulates vascular development is investigated in 3D cultures by encapsulating blood vessel organoids within viscoelastic gelatin/β‐CD assembly dynamic hydrogels or methacryloyl gelatin non‐dynamic hydrogels. The vascular organoids within the dynamic hydrogel demonstrate enhanced angiogenesis and differentiation into arterioles containing smooth muscle cells. The dynamic hydrogel mechanical microenvironment promotes vascular patterning and arteriolar differentiation by elevating notch receptor 3 signaling in mesenchymal stem cells and downregulating platelet‐derived growth factor B expression in ECs. Transplantation of vascular organoids in vivo, along with the dynamic hydrogel, leads to the reassembly of arterioles and restoration of cardiac function in infarcted hearts. These findings indicate that the viscoelastic properties of the matrix play a crucial role in controlling the vascular organization and differentiation processes, suggesting an exciting potential for its application in regenerative medicine.

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Generation of complex bone marrow organoids from human induced pluripotent stem cells

Cited by 20 publications

References 72 publications

Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of cancer driver mutations

Pre-existing stem cell heterogeneity dictates clonal responses to acquisition of cancer driver mutations

Organoids of Musculoskeletal System for Disease Modeling, Drug Screening, and Regeneration

Matrix Viscoelasticity Controls Differentiation of Human Blood Vessel Organoids into Arterioles and Promotes Neovascularization in Myocardial Infarction

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