iPSCs from people with MS can differentiate into oligodendrocytes in a homeostatic but not an inflammatory milieu

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that results in variable severities of neurodegeneration. The understanding of MS has been limited by the inaccessibility of the affected cells and the lengthy timeframe of disease development. However, recent advances in stem cell technology have facilitated the bypassing of some of these challenges. Towards gaining a greater understanding of the innate potential of stem cells from people with varying degrees of disability, we generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells derived from stable and progressive MS patients, and then further differentiated them into oligodendrocyte (OL) lineage cells.  We analyzed differentiation under both homeostatic and inflammatory conditions, via sustained exposure to low-dose interferon gamma (IFNγ), a prominent cytokine in MS. We found that all iPSCs differentiated into mature myelinating OLs, but chronic exposure to IFNγ dramatically inhibited differentiation in both MS groups, particularly if exposure was initiated during the pre-progenitor stage. Low dose IFNγ was not toxic but led to an early upregulation of interferon response genes in OPCs followed by an apparent redirection in lineage commitment from OL to a neuron-like phenotype in a significant portion of the treated cells. Our results reveal that a chronic low-grade inflammatory environment may have profound effects on the efficacy of regenerative therapies 3 Multiple Sclerosis and 2 Healthy Control iPSC lines were differentiated into oligodendrocyte precursor cells and stimulated with IFNg vs vehicle overnight

多发性硬化症（Multiple Sclerosis, MS）是一种累及中枢神经系统（central nervous system, CNS）的炎症性脱髓鞘疾病，可引发程度不一的神经退行性病变。此前学界对MS的认知受限于病变细胞难以获取，以及疾病发展周期漫长的双重瓶颈，近年来干细胞技术的进步为突破部分此类局限提供了可能。为深入探究不同残疾程度患者来源干细胞的内在潜能，本研究从稳定型与进展型MS患者的外周血单个核细胞中诱导生成多能干细胞（induced pluripotent stem cells, iPSCs），并进一步将其分化为少突胶质细胞（oligodendrocyte, OL）系细胞。我们分别在稳态与炎症条件下分析细胞分化过程：通过持续给予低剂量γ干扰素（interferon gamma, IFNγ）——这是MS中关键的促炎细胞因子——进行处理。研究发现，所有iPSCs均可分化为具备髓鞘形成能力的成熟少突胶质细胞，但慢性低剂量IFNγ暴露会显著抑制两组MS患者来源细胞的分化，尤其当暴露起始于前祖细胞阶段时，抑制效果更为突出。低剂量IFNγ并无细胞毒性，但会诱导少突胶质细胞前体细胞（oligodendrocyte precursor cells, OPCs）早期上调干扰素应答基因，随后使大量处理细胞的谱系定向发生明显重编程，从OL系转向神经元样表型。本研究结果表明，慢性低度炎症环境可能对再生治疗的疗效产生显著影响。本研究共纳入3株MS与2株健康对照iPSC系，将其分化为少突胶质细胞前体细胞后，分别给予IFNγ刺激与载体对照处理，处理时长为过夜。