Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells

Abstract

Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.

Rapid Generation of Ventral Spinal Cord-like Astrocytes from Human iPSCs for Modeling Non-Cell Autonomous Mechanisms of Lower Motor Neuron Disease

“…For instance, astrocytes involved in biological cross-talk with upper or lower motor neurons are not functionally equivalent to astrocytes found in areas of the nervous system where ALS-impacted neurons are not present. This situation is particularly evident in the spinal cord, where only astrocytes found in the ventral horn, where motor neurons are located, have the potential to affect motor neuron function and survival, as opposed to dorsally located spinal astrocytes [31]. Thus, astrocyte differentiation protocols aimed at investigating mechanisms of non-cell autonomous motor neuron degeneration in ALS must be optimized to generate cultures enriched for the most disease-relevant astrocyte subtypes.…”

“…The specialized cross-talk of defined motor neurons with particular astrocyte subtypes contributes to the different functions performed by upper and lower motor neurons, and is believed to also play roles in the mechanisms of upper or lower motor neuron degeneration [28][29][30]. Thus, understanding the contributions of human astrocytes to upper and lower motor neuron degeneration necessitates the implementation of experimental strategies that can generate pathophysiologically relevant astrocyte subtypes with the appropriate rostrocaudal and dorsoventral identities [31]. In this regard, available protocols to derive astrocytes with validated characteristics of astrocytes located in the ventral half of the spinal cord (ventral spinal cord astrocytes) are scarce and time consuming [31].…”

“…Thus, understanding the contributions of human astrocytes to upper and lower motor neuron degeneration necessitates the implementation of experimental strategies that can generate pathophysiologically relevant astrocyte subtypes with the appropriate rostrocaudal and dorsoventral identities [31]. In this regard, available protocols to derive astrocytes with validated characteristics of astrocytes located in the ventral half of the spinal cord (ventral spinal cord astrocytes) are scarce and time consuming [31].…”

Neurotoxic Astrocytes Directly Converted from Sporadic and Familial ALS Patient Fibroblasts Reveal Signature Diversities and miR-146a Theragnostic Potential in Specific Subtypes

“…Moreover, the astrocyte heterogeneity observed in ALS and other MN diseases [ 8 ] may be implicated in the difficulty in finding effective therapies for these disorders. Indeed, induced pluripotent stem cell (iPSC)-based approaches have provided increasing recognition that there are heterogeneous populations of astrocytes, highlighting the existence of subtypes and the need for patient stratification to better understand their specific roles [ 9 , 10 ]. In the present study, we aimed to explore this heterogeneity by using the trans-differentiation process of converting patient fibroblasts into induced astrocytes (iAstrocytes).…”

Comparing the potential of microglia preparations generated using different human iPSC-based differentiation methods to model microglia-mediated mechanisms of amyotrophic lateral sclerosis pathophysiology

“…A case in point: neuroinflammatory responses mediated by microglia in ALS are heterogeneous, resulting in the presence of distinct subsets of activated microglia that are believed to interact with disease-specific motor neurons in regionally-defined patterns (Dachet et al ., 2019; Maniatis et al ., 2019; Cipollina et al ., 2020; Liu et al ., 2021). More generally, the field of nervous system disease modeling using human iPSCs is increasingly recognizing the importance of including the in vivo heterogeneity of the induced cells among the factors that need to be considered when designing ideal, disease-relevant cellular assays (Hedegaard et al ., 2020; Stifani, 2021; Giacomelli et al ., 2022).…”