Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Abstract

Recent advances in the generation of microglia from human induced pluripotent stem cells (iPSCs) have provided exciting new approaches to examine and decipher the biology of microglia. As these techniques continue to evolve to encompass more complex in situ and in vivo paradigms, so too have they begun to yield novel scientific insight into the genetics and function of human microglia. As such, researchers now have access to a toolset comprised of three unique “flavors” of iPSC‐derived microglia: in vitro microglia (iMGs), organoid microglia (oMGs), and xenotransplanted microglia (xMGs). The goal of this review is to discuss the variety of research applications that each of these techniques enables and to highlight recent discoveries that these methods have begun to uncover. By presenting the research paradigms in which each model has been successful, as well as the key benefits and limitations of each approach, it is our hope that this review will help interested researchers to incorporate these techniques into their studies, collectively advancing our understanding of human microglia biology.

Emerging Developments in Human Induced Pluripotent Stem Cell-Derived Microglia: Implications for Modelling Psychiatric Disorders With a Neurodevelopmental Origin

“…This should include, for example, in vivo imaging studies of microglia-synapse interactions to complement the observations made in vitro by Sellgren and colleagues (7,83). As already mentioned, the transplantation procedure means that the microglia express a transcriptomic signature that is much closer to in vivo human microglia, as compared to culture models, even co-culture or organoid-models, although how much this influenced by the age of the host remains to be characterized in depth (38,124,127). Collectively then, experiments done using patient derived microglia and neurons in vitro may be complemented by parallel in vivo studies using chimeric models, which will likely improve the chances of results from such studies translating into effective human treatments (126).…”

“…Moreover, the chimeric model approach enables in vivo studies of how microglia derived from individuals with different psychiatric diagnosis differ from those of otherwise healthy donors. For example, it would be fascinating to study how microglia derived from individuals with SZ with high or low polygenic risk profiles, shape neurodevelopment in vivo (124,127). This should include, for example, in vivo imaging studies of microglia-synapse interactions to complement the observations made in vitro by Sellgren and colleagues (7,83).…”

Dendrimers as Modulators of Brain Cells

“…Such models are particularly suitable for investigations of the mechanisms implicated in microglia regulation upon exposure to different neuroactive agents, toxins and nanostructures including dendrimers. Aside from rodent microglia, human stem cells are valuable sources for microglia, astrocytes, oligodendrocytes, neurons and other cell types [ 49 , 50 , 51 , 52 ]. Astrocytes are essential for physiological neuronal functions, but if they acquire genetic mutations, they become highly proliferative and give rise to astrocytoma.…”

Tools and Approaches for Studying Microglia In vivo

“…Challenge 1: microglia cultured in vitro do not recapitulate in vivo microglia in their physiological environment. Although important advances have been made to develop new microglia culture methods, including serum-free culture conditions and iPSC-derived microglia [reviewed in (23)(24)(25)], in vitro approaches that reflect microglia within their immune-privileged neural environment are still lacking. Challenge 2: when studying microglia in vivo, manipulation of the CNS (for example, preparing brain slices) can lead to injury and subsequent microglia activation (26), which is a limitation for studying microglia in their physiological state.…”