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Generation of complex bone marroworganoids from human inducedpluripotent stem cells

et al. Stephanie Frenz-Wiessner

Nature Methods


The human bone marrow (BM) niche sustains hematopoiesis throughout
life. We present a method for generating complex BM-like organoids
(BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist
of key cell types that self-organize into spatially defned three-dimensional
structures mimicking cellular, structural and molecular characteristics
of the hematopoietic microenvironment. Functional properties of BMOs
include the presence of an in vivo-like vascular network, the presence
of multipotent mesenchymal stem/progenitor cells, the support of
neutrophil diferentiation and responsiveness to infammatory stimuli.

Single-cell RNA sequencing revealed a heterocellular composition
including the presence of a hematopoietic stem/progenitor (HSPC)
cluster expressing genes of fetal HSCs. BMO-derived HSPCs also exhibited
lymphoid potential and a subset demonstrated transient engraftment
potential upon xenotransplantation in mice. We show that the BMOs
could enable the modeling of hematopoietic developmental aspects and
inborn errors of hematopoiesis, as shown for human VPS45 defciency.
Thus, iPSC-derived BMOs serve as a physiologically relevant in vitro
model of the human BM microenvironment to study hematopoietic
development and BM diseases


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