Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease
Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their...
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| Veröffentlicht in: | PloS one 2022-08, Vol.17 (8), p.e0271360-e0271360 |
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| creator | Lieberman, Richard Cortes, Leslie K Gao, Grace Park, Hyejung Wang, Bing Jones, Patrick L Hunter, R. Bridge Leonard, John P Barker, Robert H |
| description | Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets. |
| doi_str_mv | 10.1371/journal.pone.0271360 |
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Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0271360</identifier><identifier>PMID: 35921286</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Accumulation ; Analysis ; Animal models ; Astrocytes ; Biology and Life Sciences ; Care and treatment ; Cell culture ; Cell survival ; Ceramide ; Ceramide glucosyltransferase ; Cytokines ; Demyelinating diseases ; Demyelination ; Diagnosis ; Enzymes ; Fibroblasts ; Galactosylceramidase ; Galactosylceramide ; Globoid cell leukodystrophy ; Glycosphingolipids ; Health aspects ; Inflammation ; Inhibitory postsynaptic potentials ; Interleukin 6 ; Kinases ; Leukodystrophy ; Lipids ; Microglia ; Mutation ; Neurons ; Neuropathology ; Oligodendrocytes ; Palmitoyltransferase ; Pathogenesis ; Pathology ; Phenotype ; Phenotypes ; Pluripotency ; Research and Analysis Methods ; Serine palmitoyltransferase ; Sphingolipids ; Stem cell transplantation ; Stem cells ; Substrates ; Survival ; White people</subject><ispartof>PloS one, 2022-08, Vol.17 (8), p.e0271360-e0271360</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Lieberman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 Lieberman et al 2022 Lieberman et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-a2996392a065220cc152fddb17489af2b1513fd8db321e1e83085e6ebd44a52c3</citedby><cites>FETCH-LOGICAL-c669t-a2996392a065220cc152fddb17489af2b1513fd8db321e1e83085e6ebd44a52c3</cites><orcidid>0000-0001-6662-5300</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348679/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348679/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids></links><search><creatorcontrib>Lieberman, Richard</creatorcontrib><creatorcontrib>Cortes, Leslie K</creatorcontrib><creatorcontrib>Gao, Grace</creatorcontrib><creatorcontrib>Park, Hyejung</creatorcontrib><creatorcontrib>Wang, Bing</creatorcontrib><creatorcontrib>Jones, Patrick L</creatorcontrib><creatorcontrib>Hunter, R. Bridge</creatorcontrib><creatorcontrib>Leonard, John P</creatorcontrib><creatorcontrib>Barker, Robert H</creatorcontrib><title>Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease</title><title>PloS one</title><description>Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.</description><subject>Accumulation</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Astrocytes</subject><subject>Biology and Life Sciences</subject><subject>Care and treatment</subject><subject>Cell culture</subject><subject>Cell survival</subject><subject>Ceramide</subject><subject>Ceramide glucosyltransferase</subject><subject>Cytokines</subject><subject>Demyelinating diseases</subject><subject>Demyelination</subject><subject>Diagnosis</subject><subject>Enzymes</subject><subject>Fibroblasts</subject><subject>Galactosylceramidase</subject><subject>Galactosylceramide</subject><subject>Globoid cell leukodystrophy</subject><subject>Glycosphingolipids</subject><subject>Health aspects</subject><subject>Inflammation</subject><subject>Inhibitory postsynaptic potentials</subject><subject>Interleukin 6</subject><subject>Kinases</subject><subject>Leukodystrophy</subject><subject>Lipids</subject><subject>Microglia</subject><subject>Mutation</subject><subject>Neurons</subject><subject>Neuropathology</subject><subject>Oligodendrocytes</subject><subject>Palmitoyltransferase</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Pluripotency</subject><subject>Research and Analysis Methods</subject><subject>Serine palmitoyltransferase</subject><subject>Sphingolipids</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Substrates</subject><subject>Survival</subject><subject>White people</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6DwQLgujFjPlo0_ZGWAZ1BxZWXPU2pMlpm7Ftukm62iv_upmZKlvZC8lFwsnzvifnkBNFzzFaY5rhtzsz2l6068H0sEYkw5ShB9EpLihZMYLowzvnk-iJczuEUpoz9jg6oWlBMMnZafTrYuxEH-tP15uVAqtvQcXCeWvk5MHFNfRghQ_BypouVqY31sU_tG_iujWl0SqW0LZxC-N3o6a9cGimWGk3tGKKhwZ646chOAnnjNQHq4M8ICAcPI0eVaJ18Gzez6KvH95_2VysLq8-bjfnlyvJWOFXghQFowURiKWEIClxSiqlSpwleSEqUuIU00rlqqQEA4acojwFBqVKEpESSc-iF0ffoTWOz71znLAiY0mK8yQQ2yOhjNjxwepO2IkbofkhYGzNhfVatsARUqqCNFUVLpMgL0slCiRTUlSJzEsRvN7N2cayAyWh91a0C9PlTa8bXptbXtAkZ1kRDF7PBtbcjOA877Tbd1r0YMb53VmSIBrQl_-g91c3U7UIBei-MiGv3Jvy8wwTyjJE00Ct76HCUtBpGT5apUN8IXizEATGw09fi9E5vr3-_P_s1bcl--oO24BofeNMO3ptercEkyMorXHOQvW3yRjx_Zz86Qbfzwmf54T-BiT6Bo0</recordid><startdate>20220803</startdate><enddate>20220803</enddate><creator>Lieberman, Richard</creator><creator>Cortes, Leslie K</creator><creator>Gao, Grace</creator><creator>Park, Hyejung</creator><creator>Wang, Bing</creator><creator>Jones, Patrick L</creator><creator>Hunter, R. 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Bridge</au><au>Leonard, John P</au><au>Barker, Robert H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease</atitle><jtitle>PloS one</jtitle><date>2022-08-03</date><risdate>2022</risdate><volume>17</volume><issue>8</issue><spage>e0271360</spage><epage>e0271360</epage><pages>e0271360-e0271360</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Globoid cell leukodystrophy (Krabbe disease) is a fatal neurodegenerative, demyelinating disease caused by dysfunctional activity of galactosylceramidase (GALC), leading to the accumulation of glycosphingolipids including psychosine. While oligodendrocytes have been extensively studied due to their high levels of GALC, the contribution of astrocytes to disease pathogenesis remains to be fully elucidated. In the current study, we generated induced pluripotent stem cells (iPSCs) from two donors with infantile onset Krabbe disease and differentiated them into cultures of astrocytes. Krabbe astrocytes recapitulated many key findings observed in humans and rodent models of the disease, including the accumulation of psychosine and elevated expression of the pro-inflammatory cytokine IL-6. Unexpectedly, Krabbe astrocytes had higher levels of glucosylceramide and ceramide, and displayed compensatory changes in genes encoding glycosphingolipid biosynthetic enzymes, suggesting a shunting away from the galactosylceramide and psychosine pathway. In co-culture, Krabbe astrocytes negatively impacted the survival of iPSC-derived human neurons while enhancing survival of iPSC-derived human microglia. Substrate reduction approaches targeting either glucosylceramide synthase or serine palmitoyltransferase to reduce the sphingolipids elevated in Krabbe astrocytes failed to rescue their detrimental impact on neuron survival. Our results suggest that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>35921286</pmid><doi>10.1371/journal.pone.0271360</doi><tpages>e0271360</tpages><orcidid>https://orcid.org/0000-0001-6662-5300</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Accumulation Analysis Animal models Astrocytes Biology and Life Sciences Care and treatment Cell culture Cell survival Ceramide Ceramide glucosyltransferase Cytokines Demyelinating diseases Demyelination Diagnosis Enzymes Fibroblasts Galactosylceramidase Galactosylceramide Globoid cell leukodystrophy Glycosphingolipids Health aspects Inflammation Inhibitory postsynaptic potentials Interleukin 6 Kinases Leukodystrophy Lipids Microglia Mutation Neurons Neuropathology Oligodendrocytes Palmitoyltransferase Pathogenesis Pathology Phenotype Phenotypes Pluripotency Research and Analysis Methods Serine palmitoyltransferase Sphingolipids Stem cell transplantation Stem cells Substrates Survival White people |
| title | Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease |
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