Aligned Brain Extracellular Matrix Promotes Differentiation and Myelination of Human-Induced Pluripotent Stem Cell-Derived Oligodendrocytes

Abstract

Myelination by oligodendrocytes (OLs) is a key developmental milestone in terms of the functions of the central nervous system (CNS). Demyelination caused by defects in OLs is a hallmark of several CNS disorders. Although a potential therapeutic strategy involves treatment with the myelin-forming cells, there is no readily available source of these cells. OLs can be differentiated from pluripotent stem cells; however, there is a lack of efficient culture systems that generate functional OLs. Here, we demonstrate biomimetic approaches to promote OL differentiation from human-induced pluripotent stem cells (iPSCs) and to enhance the maturation and myelination capabilities of iPSC-derived OL (iPSC-OL). Functionalization of culture substrates using the brain extracellular matrix (BEM) derived from decellularized human brain tissue enhanced the differentiation of iPSCs into myelin-expressing OLs. Co-culture of iPSC-OL with induced neuronal (iN) cells on BEM substrates, which closely mimics the in vivo brain microenvironment for myelinated neurons, not only enhanced myelination of iPSC-OL but also improved electrophysiological function of iN cells. BEM-functionalized aligned electrospun nanofibrous scaffolds further promoted the maturation of iPSC-OLs, enhanced the production of myelin sheath-like structures by the iPSC-OL, and enhanced the neurogenesis of iN cells. Thus, the biomimetic strategy presented here can generate functional OLs from stem cells and facilitate myelination by providing brain-specific biochemical, biophysical, and structural signals. Our system comprising stem cells and brain tissue from human sources could help in the establishment of human demyelination disease models and the development of regenerative cell therapy for myelin disorders.

Advances in Tissue Engineering and Innovative Fabrication Techniques for 3-D-Structures: Translational Applications in Neurodegenerative Diseases

“…Decellularized scaffolds can also help the differentiation of glial cells. Cho and colleagues utilized decellularized human brain tissue and found an enhancement of the differentiation of induced Pluripotent Stem Cells (iPSCs) myelin-expressing oligodendrocytes, which improved the electrophysiological properties of induced neural cells [ 135 ]. Decellularized scaffolds could also offer new opportunities for therapeutic applications in regenerative medicine.…”

Scaffolding Strategies for Tissue Engineering and Regenerative Medicine Applications

“…In fact, dECM preserves the native tissue composition, not only in terms of structural proteins as collagen, but also preserves growth factors and cytokines, which can improve cell growth and viability, and tissue repair and remodeling [15]. Further, dECM has been obtained by means of employing different processing methodologies and from a diversity of tissues, such as bone, cartilage, meniscus, tendons, skin and adipose tissue, urinary bladder, small intestinal submucosa, liver, and brain [16,17,18,19,20,21]. On the other hand, the lack of mechanical properties of those biomaterials can be overcome by means of using synthetic-based polymers or combining them with inorganic and ceramic materials to form composite structures with superior strength, osteoconductivity, and bioresorbability [22,23,24].…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…Moreover, other ECM glycoproteins play a crucial role in myelination as, for instance, anosmin-1 characterized as an important modulator of oligodendrocyte progenitor lineage progression likely via FGFR1/ERK1/2 signaling activation, which results in the control of MBP expression, myelin formation and conduction velocity (Murcia-Belmonte et al, 2016). The enhanced differentiation of induced pluripotent stem cells into myelin-expressing oligodendrocytes promoted by the functionalization of culture substrates using brain ECM prepared from decellularized human brain tissue further supports the critical activity of ECM in myelination (Cho et al, 2019).…”