Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury

Reactive astrocytes are associated with most forms of neurological disorders, ranging from acute injury to degeneration (1), and play diverse roles in these disease states. They are generally viewed as beneficial during the acute injury response and deleterious during chronic or later stages of recovery (2–7). These paradigms were initially established in spinal cord injury models, however, recent studies on astrocyte diversity have illustrated immense regional and local diversity in the adult brain suggesting that these disparate roles may be the result of a vast reservoir of reactive astrocyte populations (4, 8). When this cellular and regional complexity is met with the wide spectrum of disease states that elicit reactive astrocyte responses (7), a complex interplay between diverse resident astrocytes and disease-specific factors emerges. Therefore, deciphering how diverse reactive astrocyte responses are regulated is critical for understanding their contributions to neurological disease.

Despite their ubiquity, the molecular processes that oversee the production of reactive astrocytes after injury remain poorly defined. Critically, reactive astrocytes display a number of features that call to mind their developmental origins, including glial fibrillary acidic protein (GFAP) upregulation, increased proliferative capacity, and hypertrophy (9, 10). While these are generic features of all reactive astrocytes, using them as molecular entry points and drawing connections to their developmental origins can provide valuable insight into their diverse, post-injury functions (11). For example, STAT3 plays a key role in the generation of astrocytes during development as well as several diverse roles in reactive astrocytes. Conditional deletion of STAT3 in astrocytes impairs glial scar formation after spinal cord injury (SCI), indicating a role for STAT3 in their proliferation or migration (12). Separately, in white matter injury (WMI) models, conditional deletion of STAT3 suppressed remyelination via non–cell-autonomous mechanisms through the promotion of TGF-β1 expression in microglia (13). These observations highlight the critical contributions of factors that regulate astrocyte development to reactive astrocyte responses after injury. Moreover, they point to the diverse roles of these factors across a host of neurological disease states, suggesting that developmental factors may be a key to understanding the underlying functional diversity of reactive astrocytes.

Nuclear factor I-A (NFIA) is a transcription factor that plays a central role in astrocyte development, where it is required for the initiation of gliogenesis and the differentiation of astrocytes by direct regulation of key genes essential for astrocyte identity (14, 15). Additionally, we found that NFIA plays a key role in several neurological diseases including glioma and WMI (16–18). Studies of NFIA in WMI focused on its expression in oligodendrocyte precursor populations, finding that its ectopic expression is sufficient to suppress remyelination (18). However, whether NFIA is necessary for remyelination and the cellular origins of this function remains undefined. Critically, although NFIA is transiently expressed in oligodendrocyte precursors, it continues to be expressed in mature astrocytes in the adult brain (14–16, 18). These observations, coupled with the essential role of NFIA in astrocyte development, suggest that this transcription factor may contribute to CNS injury responses through reactive astrocytes. Currently, whether and how NFIA regulates reactive astrocyte responses after CNS injury are unknown.

To initiate studies of NFIA in reactive astrocytes, we evaluated its expression in human adult WMI and neonatal ischemic stroke and found that it was highly expressed in reactive astrocytes in both of these injury states. Combining conditional mouse genetics with spinal cord WMI models and cortical ischemic stroke models, we found that NFIA plays region- and injury-specific roles in reactive astrocytes. In the spinal cord, after WMI, NFIA-deficient astrocytes exhibited defects in blood-brain barrier (BBB) remodeling, which is correlated with the suppression of timely remyelination. In the cortex, after ischemic stroke, we found that NFIA was required for the production of reactive astrocytes from the subventricular zone (SVZ). Mechanistically, we observed that NFIA directly regulated the expression of thrombospondin 4 (Thbs4) in the SVZ, illustrating a key transcriptional node that oversees reactive astrogenesis after stroke. Together, these studies provide the initial characterization of NFIA function in reactive astrocytes after injury and show that it executes distinct functions that are both region and injury dependent. Taken more broadly, these diverse functions of a single transcription factor reinforce the importance of decoding the complex cellular and injury interplay that dictates the spectrum of reactive astrocyte responses.