Investigation of the Effects of Functionalized Fiber Tissue Scaffolds on an In Vitro Demyelination Model

Project no. 28487 · Status: Kapanmış (Yayın bekleniyor) · 2023

Summary

<p>Spinal&nbsp;cord&nbsp;injury&nbsp;(SCI)&nbsp;is&nbsp;a&nbsp;severe&nbsp;and&nbsp;debilitating&nbsp;condition&nbsp;with&nbsp;no&nbsp;current&nbsp;effective&nbsp;treatment.&nbsp;Therapeutics&nbsp;used&nbsp;in&nbsp;the&nbsp;clinic&nbsp;are&nbsp;still&nbsp;at&nbsp;an&nbsp;early&nbsp;stage&nbsp;in&nbsp;terms&nbsp;of&nbsp;successfully&nbsp;repairing&nbsp;damaged&nbsp;tissues&nbsp;and&nbsp;achieving&nbsp;full&nbsp;functional&nbsp;recovery.&nbsp;Regenerative&nbsp;strategies&nbsp;such&nbsp;as&nbsp;cell&nbsp;transplantation&nbsp;for&nbsp;tissue&nbsp;damage,&nbsp;injection&nbsp;of&nbsp;growth&nbsp;factors,&nbsp;and&nbsp;the&nbsp;use&nbsp;of&nbsp;biomaterials&nbsp;and&nbsp;stem&nbsp;cells&nbsp;have&nbsp;been&nbsp;ongoing&nbsp;for&nbsp;many&nbsp;years.&nbsp;SCI&nbsp;is&nbsp;a&nbsp;condition&nbsp;caused&nbsp;by&nbsp;mechanical&nbsp;and&nbsp;traumatic&nbsp;effects,&nbsp;leading&nbsp;to&nbsp;damage&nbsp;in&nbsp;resident&nbsp;central&nbsp;nervous&nbsp;system&nbsp;(CNS)&nbsp;cells&nbsp;such&nbsp;as&nbsp;neurons,&nbsp;astrocytes,&nbsp;and&nbsp;oligodendrocytes&nbsp;(OLs).</p><p></p><p>Damage&nbsp;to&nbsp;these&nbsp;cells&nbsp;disrupts&nbsp;neuronal&nbsp;connections,&nbsp;triggers&nbsp;inflammation,&nbsp;and&nbsp;leads&nbsp;to&nbsp;demyelination;&nbsp;however,&nbsp;remyelination&nbsp;fails&nbsp;to&nbsp;occur.&nbsp;As&nbsp;a&nbsp;result,&nbsp;the&nbsp;metabolic&nbsp;support&nbsp;normally&nbsp;provided&nbsp;by&nbsp;myelin&nbsp;sheaths&nbsp;to&nbsp;axons&nbsp;is&nbsp;lost,&nbsp;leading&nbsp;to&nbsp;progressive&nbsp;axonal&nbsp;and&nbsp;neuronal&nbsp;degeneration.&nbsp;Remyelination&nbsp;is&nbsp;a&nbsp;neuroprotective&nbsp;process&nbsp;and&nbsp;represents&nbsp;both&nbsp;an&nbsp;effective&nbsp;therapeutic&nbsp;strategy&nbsp;for&nbsp;diseases&nbsp;that&nbsp;impose&nbsp;a&nbsp;significant&nbsp;economic&nbsp;burden&nbsp;on&nbsp;society&nbsp;and&nbsp;a&nbsp;critical&nbsp;area&nbsp;of&nbsp;research&nbsp;on&nbsp;its&nbsp;own.&nbsp;Ongoing&nbsp;research&nbsp;in&nbsp;SCI&nbsp;includes&nbsp;pharmacological&nbsp;treatments,&nbsp;cell&nbsp;transplantation&nbsp;therapies,&nbsp;gene&nbsp;therapy,&nbsp;and&nbsp;tissue&nbsp;engineering&nbsp;approaches.</p><p></p><p>Recent&nbsp;advances&nbsp;in&nbsp;biotechnology&nbsp;have&nbsp;enabled&nbsp;the&nbsp;development&nbsp;of&nbsp;experimental&nbsp;studies&nbsp;in&nbsp;the&nbsp;field&nbsp;of&nbsp;spinal&nbsp;cord&nbsp;regeneration.&nbsp;From&nbsp;a&nbsp;therapeutic&nbsp;perspective,&nbsp;partial&nbsp;functional&nbsp;recovery&nbsp;in&nbsp;spinal&nbsp;cord&nbsp;injury&nbsp;may&nbsp;be&nbsp;achieved&nbsp;through&nbsp;the&nbsp;combination&nbsp;of&nbsp;several&nbsp;treatment&nbsp;strategies,&nbsp;leading&nbsp;to&nbsp;improvements&nbsp;in&nbsp;patients’&nbsp;quality&nbsp;of&nbsp;life.&nbsp;Polymeric&nbsp;tissue&nbsp;scaffolds&nbsp;have&nbsp;long&nbsp;been&nbsp;used&nbsp;in&nbsp;biomaterial-based&nbsp;approaches&nbsp;through&nbsp;functionalization.</p><p></p><p>As&nbsp;a&nbsp;novel&nbsp;therapeutic&nbsp;approach,&nbsp;a&nbsp;biomaterial-based&nbsp;treatment&nbsp;option&nbsp;functionalized&nbsp;by&nbsp;incorporating&nbsp;CRISPR/Cas9&nbsp;complexes&nbsp;into&nbsp;injectable&nbsp;hydrogels&nbsp;has&nbsp;been&nbsp;validated&nbsp;to&nbsp;induce&nbsp;<em>in&nbsp;vitro</em>&nbsp;myelination.</p><p></p><p>As&nbsp;remyelination-inducing&nbsp;agents,&nbsp;ADAM8-KO&nbsp;and&nbsp;SERPINE1-KO&nbsp;CRISPR/gRNAs,&nbsp;which&nbsp;are&nbsp;expected&nbsp;to&nbsp;have&nbsp;effects&nbsp;on&nbsp;myelin,&nbsp;were&nbsp;used.&nbsp;While&nbsp;ADAM8-KO&nbsp;application&nbsp;did&nbsp;not&nbsp;significantly&nbsp;affect&nbsp;the&nbsp;expression&nbsp;of&nbsp;inflammation-related&nbsp;genes&nbsp;in&nbsp;oligodendrocytes,&nbsp;it&nbsp;showed&nbsp;a&nbsp;limited&nbsp;myelin-supportive&nbsp;effect,&nbsp;reflected&nbsp;only&nbsp;by&nbsp;an&nbsp;increase&nbsp;in&nbsp;MBP&nbsp;gene&nbsp;expression.&nbsp;In&nbsp;contrast,&nbsp;SERPINE1-KO&nbsp;increased&nbsp;the&nbsp;expression&nbsp;of&nbsp;all&nbsp;major&nbsp;myelin-related&nbsp;genes&nbsp;(MBP,&nbsp;MOG,&nbsp;CNP),&nbsp;demonstrating&nbsp;that&nbsp;it&nbsp;promotes&nbsp;the&nbsp;formation&nbsp;of&nbsp;a&nbsp;more&nbsp;stable&nbsp;and&nbsp;remyelination-supportive&nbsp;microenvironment&nbsp;through&nbsp;extracellular&nbsp;matrix&nbsp;remodeling&nbsp;and&nbsp;the&nbsp;removal&nbsp;of&nbsp;degenerative&nbsp;factors.</p><p></p><p>This&nbsp;study&nbsp;contributes&nbsp;to&nbsp;the&nbsp;development&nbsp;of&nbsp;CRISPR/Cas9-based&nbsp;modulatory&nbsp;therapeutics&nbsp;aimed&nbsp;at&nbsp;reducing&nbsp;adverse&nbsp;effects&nbsp;on&nbsp;oligodendrocytes.&nbsp;As&nbsp;a&nbsp;novel&nbsp;therapeutic&nbsp;approach,&nbsp;hydrogels&nbsp;functionalized&nbsp;with&nbsp;SERPINE1-suppressing&nbsp;CRISPR/Cas9&nbsp;exhibit&nbsp;remyelination&nbsp;potential.</p>

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