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Background <p>Mouse and human astrocytes exhibit substantial species-specific differences in both morphology and function. Their response to inflammatory stimuli, however, remains underexplored despite being crucial for understanding bidirectional astrocyte-neuron signaling dynamics and for translating preclinical findings to human-relevant applications. Induced pluripotent stem cell-based models thus offer a powerful platform to investigate these mechanisms in the context of the human neural connectome.</p> Methods <p>We apply two well-established in vitro protocols by exposing cultured astrocytes to lipopolysaccharide (LPS) for either 3 or 24&#xa0;h to trigger an inflammatory response. We investigated how LPS-induced inflammation affects the endogenous Ca<sup>2+</sup> activity in astrocytes derived from the mouse hippocampus (HC) and prefrontal cortex (PFC), as well as human induced pluripotent stem cell (hiPSC)-derived astrocytes. Both, morphological changes and Ca<sup>2+</sup> activity were analyzed using the volume fraction (VF) approach and our previously developed multi-threshold event detection (MTED) combined with machine learning-driven non-negative matrix factorization (NMF).</p> Results <p>The comprehensive assessment of Ca<sup>2+</sup> activity patterns and their relation to cell morphology revealed significant alterations in response to LPS treatment, and further between mouse and human hiPSC-derived astrocytes. While both mouse and human astrocytes show increased Ca<sup>2+</sup> event frequency after short-term LPS exposure, after 24&#xa0;h of LPS treatment Ca<sup>2+</sup> activity is severely restricted in PFC astrocytes but substantially increased in human astrocytes.</p> Conclusions <p>Our findings highlight the unique properties of human iPSC-derived astrocytes and provide detailed insights into how Ca<sup>2+</sup> signaling becomes dysregulated under neuroinflammatory conditions. Understanding the species-specific responses is essential for advancing stem cell-based models of human astrocyte-neuron signaling circuits and for developing targeted therapeutic strategies to alleviate neuroinflammation and Ca<sup>2+</sup>-related dysregulation in neurological diseases.</p>

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LPS-induced inflammation differentially affects endogenous Ca2⁺ activity in mouse and human iPSC-derived astrocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Franziska E. Müller,
  • Flavian Ivanov,
  • Anne-Catharine Studt,
  • Ida Nitzsche,
  • Frauke S. Bahr,
  • Anna-Lena Krüger,
  • Josephine Labus,
  • Ghanendra Singh,
  • Evgeni G. Ponimaskin,
  • Kerstin Lenk,
  • Andre Zeug

摘要

Background

Mouse and human astrocytes exhibit substantial species-specific differences in both morphology and function. Their response to inflammatory stimuli, however, remains underexplored despite being crucial for understanding bidirectional astrocyte-neuron signaling dynamics and for translating preclinical findings to human-relevant applications. Induced pluripotent stem cell-based models thus offer a powerful platform to investigate these mechanisms in the context of the human neural connectome.

Methods

We apply two well-established in vitro protocols by exposing cultured astrocytes to lipopolysaccharide (LPS) for either 3 or 24 h to trigger an inflammatory response. We investigated how LPS-induced inflammation affects the endogenous Ca2+ activity in astrocytes derived from the mouse hippocampus (HC) and prefrontal cortex (PFC), as well as human induced pluripotent stem cell (hiPSC)-derived astrocytes. Both, morphological changes and Ca2+ activity were analyzed using the volume fraction (VF) approach and our previously developed multi-threshold event detection (MTED) combined with machine learning-driven non-negative matrix factorization (NMF).

Results

The comprehensive assessment of Ca2+ activity patterns and their relation to cell morphology revealed significant alterations in response to LPS treatment, and further between mouse and human hiPSC-derived astrocytes. While both mouse and human astrocytes show increased Ca2+ event frequency after short-term LPS exposure, after 24 h of LPS treatment Ca2+ activity is severely restricted in PFC astrocytes but substantially increased in human astrocytes.

Conclusions

Our findings highlight the unique properties of human iPSC-derived astrocytes and provide detailed insights into how Ca2+ signaling becomes dysregulated under neuroinflammatory conditions. Understanding the species-specific responses is essential for advancing stem cell-based models of human astrocyte-neuron signaling circuits and for developing targeted therapeutic strategies to alleviate neuroinflammation and Ca2+-related dysregulation in neurological diseases.