title: Generation of cortical neurons from human induced-pluripotent stem cells by biodegradable polymeric microspheres loaded with priming factors.
abstract: Ischemic stroke is often associated with loss of cortical neurons leading to various neurological deficits. A cell replacement based on stem cell transplantation to repair the damaged brain requires the generation of specific neuronal subtypes. Recently, induced pluripotent stem cells have been used to generate various subtypes of neurons in vitro for transplantation in stroke-damaged brains. However, whether these cells can be primed as neuronal precursors to become cortical projection neurons by means of biomaterials releasing differentiation factors is not known. Here, we report that microspheres of biodegradable poly(ester-amide) composed of adipic acid, L-phenyl-alanine and 1,4-butanediol, loaded with differentiation factors, can be used to fate human induced pluripotent stem cell-derived long-term expandable neuroepithelial-like stem cells to cortical projection neurons. The three factors, Wnt3A, BMP4 and cyclopamine, were released from loaded microspheres over at least one month following biphasic dynamic time course, promoting cortical differentiation of the cells in vitro. Microspheres did not evoke significant inflammatory response after transplantation into intact rodent brain. Our study shows the potential of biodegradable polymer microspheres to promote neuronal differentiation by continuous release of factors, thereby creating the appropriate microenvironment. This new strategy may improve the efficacy of stem cell-based therapeutic approaches.
authors.affiliation: Laboratory of Stem Cell and Restorative Neurology, Lund Stem Cell Center, University Hospital, Lund 22184, Sweden.
authors.forename: Tamar
authors.initials: T
authors.lastname: Memanishvili
authors.forename: Nino
authors.initials: N
authors.lastname: Kupatadze
authors.forename: David
authors.initials: D
authors.lastname: Tugushi
authors.forename: Ramaz
authors.initials: R
authors.lastname: Katsarava
authors.forename: Somsak
authors.initials: S
authors.lastname: Wattananit
authors.forename: Naomi
authors.initials: N
authors.lastname: Hara
authors.forename: Daniel
authors.initials: D
authors.lastname: Tornero
authors.forename: Zaal
authors.initials: Z
authors.lastname: Kokaia
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D055415:Bone Morphogenetic Protein 4 / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016503:Drug Delivery Systems; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation; D008422:Materials Testing; D008863:Microspheres; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D011091:Polyesters / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000628:therapy; D014704:Veratrum Alkaloids / Q000008:administration & dosage; D060509:Wnt3A Protein / Q000008:administration & dosage
chemical_list: C525809:BMP4 protein, human; D001672:Biocompatible Materials; D055415:Bone Morphogenetic Protein 4; D011091:Polyesters; D014704:Veratrum Alkaloids; D060509:Wnt3A Protein; C000541:cyclopamine