Ependymal cell contribution to scar formation after spinal cord injury is minimal, local and dependent on direct ependymal injury

Abstract

Ependyma have been proposed as adult neural stem cells that provide the majority of newly proliferated scar-forming astrocytes that protect tissue and function after spinal cord injury (SCI). This proposal was based on small, midline stab SCI. Here, we tested the generality of this proposal by using a genetic knock-in cell fate mapping strategy in different murine SCI models. After large crush injuries across the entire spinal cord, ependyma-derived progeny remained local, did not migrate and contributed few cells of any kind and less than 2%, if any, of the total newly proliferated and molecularly confirmed scar-forming astrocytes. Stab injuries that were near to but did not directly damage ependyma, contained no ependyma-derived cells. Our findings show that ependymal contribution of progeny after SCI is minimal, local and dependent on direct ependymal injury, indicating that ependyma are not a major source of endogenous neural stem cells or neuroprotective astrocytes after SCI.

Cell biology of spinal cord injury and repair

“…5,13). This scar border formation is complete by 2 to 3 weeks after SCI and consists almost entirely of newly proliferated astrocytes (13,14). Astrocyte Figure 1A; Figure 2, A and B; and refs.…”

“…Astrocyte scar borders are intermingled with reactive oligodendrocyte progenitor cells (OPC) that express chondroitin sulfate proteoglycan 4 (also known as neuron glial antigen 2 [NG2]), and these cells are often referred to as NG2-OPC ( Figure 1A). The lineage derivation of newly proliferated scar-forming astrocytes is not completely defined, but many if not most appear to derive from proliferation of local astrocytes (17) and not from putative ependymal progenitor cells (14). Genomic profiles of astrocytes and nonastrocyte cells in mature SCI lesions have recently been evaluated by RNA sequencing (19), and data for individual genes are available in a searchable open-access website (https://astrocyte.rnaseq.…”

The diversity and disparity of the glial scar

“…Interestingly, this proliferative population of reactive astrocytes was also shown by clonal analysis to be derived from distinct progenitors 20 , suggesting that one source of reactive astrocyte heterogeneity may be distinct cellular origins. In support of this, neural stem cell (NSC)-derived reactive astrocytes have been shown to contribute to glial scars in the brain 21 , while a recent study found little contribution of NSC-derived reactive astrocytes to SCI-induced glial scars 22 . Therefore, reactive astrocyte heterogeneity is dependent on the site of injury.…”

Unlocking the paradoxical endogenous stem cell response after spinal cord injury

“…Recent work has challenged the conventional view that SCI induces a robust ependymal cell response that contributes to the glial scar. Using a FoxJ1‐KI‐CreERT2‐TdTomato mouse model as a lineage‐tracing tool for FoxJ1‐expressing ependymal cells, Ren et al found that ependymal NSPCs have a minimal reactive response after SCI and contribute little to the glial scar . This finding may in part be due to differences in the transgenic mouse models used in these studies.…”