Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.
Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.
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DOI：
10.1371/journal.pntd.0011477
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发表时间：
2023-07
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
麻风杆菌优先感染周围神经中的雪旺细胞(SCs)，导致神经损伤和不可逆转的残疾。了解麻风杆菌是如何感染和与宿主干细胞相互作用的，对于了解神经损伤的机制和揭示潜在的新治疗策略是至关重要的。我们对不同时间点感染麻风杆菌的干细胞进行了时程单细胞测序分析，进一步分析了干细胞的异质性、与麻风杆菌感染相关的亚群、干细胞的发育轨迹，并通过Western印迹或流式细胞术进行了验证。不同的干细胞亚群表现出不同的遗传特征和功能丰富。我们观察到与麻风杆菌感染相关的两个亚群，干细胞样细胞亚群在麻风杆菌感染后24小时显著增加，但在感染后72小时下降，脂肪细胞亚群在感染后72小时出现。结果证实干细胞样细胞亚群处于分化的早期阶段，可以分化为脂肪细胞样细胞亚群。我们的结果在单细胞分辨率下对麻风杆菌感染后SC的异质性进行了系统的时程分析，为了解麻风杆菌感染SCs过程中潜在的重编程和脂代谢的关键生物学过程提供了有价值的信息，并增加了对麻风患者致病机制的理解，以及揭示了潜在的新的治疗策略。麻风病仍然是世卫组织的一个主要公共卫生关切问题，尤其影响到世界最不发达国家最贫穷和处境最不利的社会阶层。探索麻风神经损伤的机制，以预防畸形和残疾的发生，引起了科学家的极大兴趣和广泛关注。虽然已经取得了一些成果，但作为麻风杆菌繁殖的关键阶段，对麻风杆菌感染人干细胞早期发生的事件仍知之甚少。在这项研究中，我们的目标是在单细胞分辨率下研究麻风杆菌感染不同阶段的SC异质性和生物标志物。我们发现干细胞样细胞亚群处于分化的早期阶段，可以分化为脂肪细胞样细胞亚群。这项研究为研究麻风杆菌调控宿主细胞分化和代谢的动态过程提供了一个新的视角，从而增加了对麻风患者致残原因的潜在机制的理解，并确定了潜在的新治疗策略。
M. leprae preferentially infects Schwann cells (SCs) in the peripheral nerves leading to nerve damage and irreversible disability. Knowledge of how M. leprae infects and interacts with host SCs is essential for understanding mechanisms of nerve damage and revealing potential new therapeutic strategies. We performed a time-course single-cell sequencing analysis of SCs infected with M. leprae at different time points, further analyzed the heterogeneity of SCs, subpopulations associated with M. leprae infection, developmental trajectory of SCs and validated by Western blot or flow cytometry. Different subpopulations of SCs exhibiting distinct genetic features and functional enrichments were present. We observed two subpopulations associated with M. leprae infection, a stem cell-like cell subpopulation increased significantly at 24 h but declined by 72 h after M. leprae infection, and an adipocyte-like cell subpopulation, emerged at 72 h post-infection. The results were validated and confirmed that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. Our results present a systematic time-course analysis of SC heterogeneity after infection by M. leprae at single-cell resolution, provide valuable information to understand the critical biological processes underlying reprogramming and lipid metabolism during M. leprae infection of SCs, and increase understanding of the disease-causing mechanisms at play in leprosy patients as well as revealing potential new therapeutic strategies. Leprosy remains a key public health concern for WHO, particularly affecting the poorest and most disadvantaged sectors of society in the world’s least developed countries. The exploration of the mechanism of leprosy nerve injury in order to prevent the occurrence of deformity and disability has aroused great interest and extensive attention of scientists. Although some achievements have been made, as a critical phase for the propagation of M. leprae, events occurring during the early stage of M. leprae infection of human SCs are still poorly understood. In this study, we aimed to investigate SC heterogeneity and biomarkers in different M. leprae infectious stages at a single cell resolution. We established that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. This research provides a novel perspective on the dynamic process of host cell differentiation and metabolism regulated by M. leprae and thus increase understanding of the mechanisms underlying the causes of disability in leprosy patients as well as identifying potential new therapeutic strategies.
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