Direct Differentiation of Human Adult Adipose Tissue into Multilineage Functional Organoids

Current organoid-generation strategies rely predominantly on intricate in vitro manipulations of dissociated stem cells, including isolation, expansion, and genetic modification. However, these approaches present significant challenges in terms of safety and scalability for clinical applications. An alternative strategy involves the direct generation of organoids from readily available tissues. Herein, we report the generation of functional organoids representing all three germ layers from human adult adipose tissue without single-cell processing steps. Specifically, by employing a specialized suspension culture system, we have developed reaggregated microfat (RMF) tissues, which differentiated into mesodermal bone marrow organoids capable of reconstituting human normal hematopoiesis in immunodeficient mice, endodermal insulin-producing organoids that reversed hyperglycemia in streptozotocin (STZ)-induced diabetic mice, and ectodermal nervous-like tissues resembling neurons and neuroglial cells. These findings therefore highlight the potential of human adipose tissue as a safe, scalable, and clinically viable source for organoid-based regenerative therapies.