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Human induced pluripotent stem cell-derived neurons and coculture conditions regulate the adipogenic differentiation and functionality of human adipose stromal/stem cells

Sini Saarimaa,Miia Juntunen,Lotta Isosaari,Reija Autio,Marika Kuuskeri,Susanna Narkilahti,Susanna Miettinen

Published 2025 in Cell Communication and Signaling

ABSTRACT

The obesity epidemic and associated diseases have increased the need to study human adipose tissue biology and, furthermore, the development of in vitro models of adipose tissues. Human adipose tissue innervation is a relatively understudied research area, and most studies have been performed in animal models. A common animal model is the mouse, which differs from humans in many areas, such as fat distribution, metabolism and genetics. Here, our aim was to develop a three-dimensional (3D) neuro-adipose in vitro model with human-derived cells to deepen the understanding of adipose tissue innervation. We hypothesized that our novel, optimized coculture conditions for neurons and adipose stromal/stem cells (ASCs) would enhance the adipogenesis of ASCs and the functionality of differentiating ASC-derived adipocytes. In this study, a novel 3D in vitro culture of adipocytes innervated on a microfluidic chip utilizing human ASCs and human induced pluripotent stem cell (hiPSC)-derived neurons was established. The cells were cultured in a fibrin–collagen 1 hydrogel in a microfluidic environment for a long period (≥ 21 days) in neuro-adipose combination medium (NM-AM). The adipogenic differentiation of ASCs and adipose cell functions, such as fatty acid (FA) uptake, lipolysis and adipokine secretion, were analyzed. In addition, cell activity was examined with calcium activity measurements, and cell connections were examined with immunocytochemistry and 3D confocal imaging. The adipogenic differentiation of ASCs was significantly increased in NM-AM compared with adipogenic differentiation medium (AM) and differentiation was further enhanced by the neurons in the cocultures. Neurons formed synapses with each other as well as innervated ASCs. Both ASCs and neurons showed typical calcium activity in monocultures and cocultures. Neurons enhanced the FA uptake of ASCs while simultaneously decreasing the lipolysis of ASCs in cocultures. In addition, differentiating ASCs secreted adipokines and acetylcholine in mono- and cocultures. This research provides a novel human cell-based 3D in vitro model to study adipose tissue innervation and neuro-adipose interactions. Here, the novel human cell-based coculture model holds great potential for future mechanistic studies of neuro-adipose regulation.

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