A Human Model of Oligodendrocyte Development Shows <scp>MCL</scp> ‐1 Influences Oligodendrocyte Morphogenesis

Oligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically, myelin sheath formation is an energetically demanding event that requires precision, as alterations may lead to dysmyelination. Fatty acid β-oxidation has been shown to be critical for the function of oligodendrocytes. We previously showed that myeloid cell leukemia-1 (MCL-1), a well-characterized anti-apoptotic protein, is required for the development of murine oligodendrocytes in vivo. Further, MCL-1 regulates long-chain fatty acid β-oxidation in cancer cells through its interaction with Acyl-CoA synthetase long-chain family member 1 (ACSL1), an enzyme responsible for the conversion of free long-chain fatty acids into fatty acyl-CoA esters. Here, we introduce an in vitro system to isolate human stem cell-derived oligodendrocyte progenitor cells (OPCs) and investigate the involvement of MCL-1 during human oligodendrocyte development. Using this system, we pharmacologically inhibited MCL-1 in OPCs to investigate its non-apoptotic function at this developmental stage. We also used a motor neuron-oligodendrocyte co-culture system to examine the downstream effects of MCL-1 at later developmental stages when oligodendrocytes begin to contact axons and generate myelin. We demonstrate that the mitochondrial network changes in human oligodendrocyte development resemble those reported in mouse tissue. Our findings point to MCL-1 as a critical factor essential for proper oligodendrocyte morphogenesis.