Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease

Abstract

Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

“…4C) indicative of increased "anxiety-like" behavior in the hexb−/−mice. We have employed a behavioral test battery to assess a mouse model of Sandhoff disease that we backbred onto the C57BL/6J background.We demonstrated deficits in motor activity, and coordination consistent with those previously reported [1,7,8,13,14,16,18,20,22,25,27,28] suggesting no significant effect of genetic background. However, we were also able to detect deficits as early as 66 days using the balance beam test.…”

“…Furthermore, the fact that all mice improve with successive trials in the rotarod and that the motor incoordination was worse in the harder balance beam task would tend to argue against solely peripheral causes, such as muscle wasting and hind limb rigidity. Finally, the deficits in motor coordination and/or learning are in accord with the neuronal loss and cellular pathology reported in the cerebellum, basal ganglia and striatum [16,18,22,25,28].The age of onset of motor deficits previously reported has widely varied, even when the same test was employed, such as the rotarod [18,20,22,25,27,28] or horizontal beam crossing test [1,4,[13][14][15], in which deficits were first detected as late as 104 days [13].Varied findings for the same test may be attributable to different genetic backgrounds (the original mice were not purebred and colony breeding schemes have differed between reports) and/or to different experimental parameters. Evidence for onset of motor incoordination as early as 60-70 days in LSDs, as we have detected using the balance beam test, is uncommon [15,27,28].…”

“…The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20]. The knockout model [25] presented here displays ataxia, tremor, muscle wasting, and deficits in motor reflex, coordination and balance [1,4,7,8,13,14,16,18,20,22,25,27,28].…”

“…Both latency (time to cross the beam from end to end) and number of slips (each time a paw fell under the beam midline) were assessed as measures of motor coordination. In the rotarod test, latency to fall from a rotating rod (acceleration increased by 0.5 cm/s every 5 s) was scored automatically with infrared sensors in a Rotamex 5 rotarod (Columbus Inst, Ohio) with four trials per day over 2 days.Behavioral tests were primarily conducted on mice of 79(±2) days old, an age that in most previous assays showed no deficits, but were also performed on some at 66(± 2) and 97(± 2) days when had been typically reported as normal or displaying deficits, respectively [1,4,7,8,13,14,16,18,20,22,25,27,28]. All data are shown as mean ± S.E.M.…”

Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

“…In addition to neuroprotective effects, NSPCs are known to have immunomodulative effects 4,19,24 ; therefore, the acute inflammatory response after NSPC transplantation was also examined. Although increased expression of anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor beta 1 (TGF-β1) was observed, no significant differences were observed in terms of the expression of pro-inflammatory cytokines or the number of infiltrating inflammatory cells (Fig.…”