Abstract
Neural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato mice demonstrated that Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSCs expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.
Highlights
Transplantation of stem cells into specific locations in the central nervous system (CNS) parenchyma may be the most appropriate approach for testing restorative cell therapies for focal lesions, such as stroke or Parkinson’s disease
In both traumatic brain injury (TBI) and sham mice, TMX administered after surgery induced sonic hedgehog (Shh)-tdTomato fluorescent protein (Tom) labeling predominantly in neuronal cell bodies, axons, and processes based on morphology and immunolabeling for NeuN (Figures 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), and S2)
The Gli1 genetic labeling approach used in the current study is a specific indicator of active in vivo signaling through the canonical Shh pathway, Shh can act through noncanonical mechanisms that do not require Gli1 activation [41, 42]. These studies demonstrate that adult Neural stem cells (NSCs) transplanted into the lateral ventricle remain within the lateral and third ventricles for at least two weeks and significantly reduce neuroinflammation in the corpus callosum
Summary
Transplantation of stem cells into specific locations in the central nervous system (CNS) parenchyma may be the most appropriate approach for testing restorative cell therapies for focal lesions, such as stroke or Parkinson’s disease. Diffuse injuries such as traumatic brain injury (TBI) may require approaches that can reach broader regions. Diffuse axonal injury in white matter tracts is the most common pathological feature of TBI [1, 2]. NSCs transplanted within the ventricular system may interact dynamically with endogenous cells to attenuate neuroinflammation, which contributes to a cascade of secondary damage in white matter tracts.
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