PAX6-positive microglia (PPM) evolve locally in hiPSC-derived ocular organoids
Microglia are located in the central nervous system (CNS) and are the innate immune system cells that are responsible for protecting the retina. However, it is not known how microglia develop in the eye. In this study, Shiraki et al. examined human-induced pluripotent stem cells (hiPSCs) that had been expanded into SEAM (self-formed ectodermal autonomous multi-zone) cells, which partially mimic the growth of the human eye. Their results showed that microglia-like cells grow naturally in two-dimensional SEAM-like organoids that lack any vascular components. These cells are unique in that they encode the PAX6 protein, yet they possess some properties of mesoderm. Collectively, the data show the existence of a isolated and locally developing immune system in the eye that is independent of the body's arteries and the general immune system.
In this study, we provided the possibility that ocular microglia-like cells emerge naturally and locally in the eye and are PAX6-positive. In this study, hiPSCs form 2D SEAM-like organoids and show that SEAM cells contain PPM cells that appear spontaneously under simple and natural differentiation in the absence of any factor that mimics circulation. Thus, PPM cells grow in the absence of vessels in hiPSC-derived SEAM organoids.
Stimulation of PPM cells by lipopolysaccharides (LPS) did not elicit any cytokine response, and in this respect, they are unlike normal microglia and therefore PPM cells are distinct from bone marrow or mesoderm-derived microglia. Also, PPM cells and immortalized human microglia cells have different responses to inflammatory stimulation.
Further attempts at maturation and examination of PPM functions may contribute to a better understanding of the immune system of the eye. In this study, a two-dimensional model was used and a three-dimensional model of the whole eye (including cornea, conjunctiva, retina, retinal pigment epithelium, lens, etc.) has not yet been developed. The development of a three-dimensional model of the eye development allows a more complete examination of its immune system.
PAX6 is considered to be an ocular master control gene and is essential for eye development. This gene is required for the differentiation of most retinal lineages, and when it is inactivated in retinal precursor cells, they do not form retinal cells. In addition, PAX6 is essential for the differentiation of human embryonic stem cells (ESCs) into neuroectoderm, and is a factor in the general neuroectodermal characterization of mammals. Thus, PPM cells appearing in hiPSC-derived SEAMs are probably of neuroectodermal origin, but they also have some of the characteristics of mesoderm cells. This suggests that some retinal microglia are cells derived from neuroectoderm and retain some of the properties of the mesoderm. These findings significantly increase our understanding of the origin of the microglia that regulate the CNS immune system, particularly the retina, as well as the possibility of developing a local immune system involving cells such as macrophages residing in the brain or other organs.
https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(21)00648-2
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