Concepts toward directing human astroplasticity to promote neuroregeneration

Abstract

Astrocytes exhibit dynamic and complex reactions to various insults. Recently, investigations into the transitions that occur during cellular specification, differentiation, maturation, and disease responses have provided insights into understanding the mechanisms that underlie these altered states of reactivity and function. Here we summarize current concepts in how astrocyte state transitions, termed astroplasticity, are regulated, as well as how this affects neural circuit function through extracellular signaling. We postulate that a promising future approach toward enhancing functional repair after injury and disease would be to steer astrocytes away from an inhibitory response and toward one that is beneficial to neuroplasticity and neuroregeneration. Toward this goal, we discuss emerging biotechnological advancements, with a focus on human pluripotent stem cell bioengineering, which has high potential for effective manipulation and control of astroplasticity. Highlights include innovations in cellular transdifferentiation techniques, nanomedicine, organoid and three-dimensional (3D) spheroid microcircuit development, and the use of biomaterials to influence the extracellular environment. Current barriers and future applications are also summarized in order to augment the design of future preclinical trials aimed toward astrocyte-targeted neuroregeneration with a concept termed astrocellular therapeutics.

Assessing Gq-GPCR–induced human astrocyte reactivity using bioengineered neural organoids

“…Defining reactivity of astrocytes within distinct contexts is necessary to better understand their relationship with neuronal networks and to identify therapeutic targets, such as GPCRs, for manipulating reactivity states ( Patel et al, 2019 ; Escartin et al, 2021 ). Despite providing improvements over monolayer culture approaches and variable neural organoid systems, the bioengineering innovations described in this study undoubtedly contain remaining caveats.…”

Asteroid impact: the potential of astrocytes to modulate human neural networks within organoids

“…For over a decade, astrocytes derived from human pluripotent stem cells (hPSCs) have been used as a cellular source to further understand basic neurobiology at the molecular and cellular levels, as well as for disease modeling, as we (Krencik et al, 2011(Krencik et al, , 2015Krencik and Ullian, 2013;Patel et al, 2019) and others (Li and Shi, 2020;Bigarreau et al, 2022;Kumar et al, 2022;Jovanovic et al, 2023) have previously described. However, major caveats remain to be addressed in the traditional methods for astrocyte generation, including the inconsistent choice of differentiation timepoints to conduct studies, cell culture medium components, stress induced by cellular dissociation, use of synthetic substrates that can alter functionality, and lack of neurons and other cell types that contribute intercellular signals for astrocyte physiological maturity.…”

Special issue on stem cell and tissue engineering in development, disease, and repair

“…In this special issue, several manuscripts specifically discuss the use of stem cells for disease modeling. Robert Krencik and colleagues discuss the plastic properties of astrocytes, which allow them to react to different surroundings, and how these properties could be harnessed to promote regeneration of neurons (Patel et al, ). They also review different protocols available for producing human astrocytes from iPSCs.…”