{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T11:36:32Z","timestamp":1771068992648,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T00:00:00Z","timestamp":1150675200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2006,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a \u2018sick\u2019 cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the <jats:italic>twitcher<\/jats:italic> (<jats:italic>twi\u200a<\/jats:italic>) mouse \u2013 as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model \u2013 loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. <jats:italic>Twi<\/jats:italic> mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine\u2010filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile\/young adult <jats:italic>twi<\/jats:italic> mice, we have determined that widespread oligodendrocyte replacement and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine \u2013 more so in their undifferentiated state than when directed <jats:italic>ex vivo<\/jats:italic> to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over\u2010express GalC. Some <jats:italic>twi<\/jats:italic> mice grafted with such engineered NSCs had thicker white tracts and lived 2\u20133 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in <jats:italic>twi<\/jats:italic> mice that died at a younger age. This concept of resistance based on differentiation state extended to human NSCs which could similarly survive within the <jats:italic>twi<\/jats:italic> brain. Taken together, these results suggest a number of points regarding cellular therapies against degenerative diseases with a prominent cell non\u2010autonomous component: Cell replacement is possible if cells resistant to the toxic environment are employed. Furthermore, an important aspect of successful treatment will likely be not only cell replacement but also cross\u2010correction of host cells to provide them with enzyme activity and hence resistance. While oligodendrocyte replacement alone was not a sufficient treatment for GLD (even when extensive), the replacement of both cells <jats:italic>and<\/jats:italic> molecules \u2013 e.g. with NSCs that could both become oligodendrocytes and \u2018pumps\u2019 for GalC \u2013 emerges as a promising basis for a multidisciplinary strategy. Most neurological disease are complex in this way and will likely require multifaceted approaches, perhaps with NSCs serving as the \u2018glue\u2019.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03986.x","type":"journal-article","created":{"date-parts":[[2006,6,19]],"date-time":"2006-06-19T11:43:05Z","timestamp":1150717385000},"page":"1585-1599","source":"Crossref","is-referenced-by-count":49,"title":["Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non\u2010autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy"],"prefix":"10.1111","volume":"97","author":[{"given":"Roseanne M.","family":"Taylor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean Pyo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James J.","family":"Palacino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate A.","family":"Bower","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxue","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie T.","family":"Vanier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Wenger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L.","family":"Sidman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan Y.","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,6,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.23.12846"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022438099"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.16.6368"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01670"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/103.3.695"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa042604"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/3473"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4366-05.2006"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408258102"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awg089"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00900"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1021202"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(80)90159-6"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506473102"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0496-424"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01734"},{"key":"e_1_2_7_18_1","doi-asserted-by":"crossref","first-page":"6841","DOI":"10.1128\/JVI.73.8.6841-6851.1999","article-title":"Neural stem cells as engraftable packaging lines optimize viral vector\u2010mediated gene delivery to the CNS: evidence from studying retroviral env\u2010related neurodegeneration","volume":"73","author":"Lynch W. 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