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Khóa đặc hiệu Protein Morphogenetic xương-2/4 Kích thích Oligodendrogenesis và Remyelination trong các Rối loạn Demyelinating
Tóm tắt
Các tế bào tiền thân oligodendrocyte (OPC) có mặt trong các tổn thương không myelin hóa ở bệnh nhân đa xơ cứng (MS). Tuy nhiên, sự phân hóa của chúng thành oligodendrocyte chức năng là không đủ, và hầu hết các tổn thương tiến triển thành sẹo astroglial không chức năng. Khóa tín hiệu protein morphogenetic xương (BMP) kích thích sự phân hóa của OPC thành oligodendrocyte sản xuất myelin. Chúng tôi đã nghiên cứu tác động của việc khóa cụ thể tín hiệu BMP-2/4, thông qua điều trị tĩnh mạch (IV) với kháng thể trung hòa anti-BMP-2/4 trong cả mô hình viêm của bệnh viêm não tự miễn tái phát (R-EAE) và mô hình độc tính cuprizone gây ra mất myelin ở chuột. Việc tiêm anti-BMP-2/4 vào chuột R-EAE, vào ngày thứ 9 sau khi tiêm chủng (p.i.), đã cải thiện các dấu hiệu của R-EAE, giảm sự biểu hiện của phospho-SMAD1/5/8, chủ yếu trong dòng tế bào astrocyte, tăng số lượng oligodendrocyte chưa trưởng thành và trưởng thành mới, và giảm số lượng astrocyte mới hình thành trong tủy sống ngay từ ngày 18 p.i. Tác động này được đi kèm với gia tăng remyelination, được biểu hiện bởi tăng mật độ của các sợi trục đang remyelinating (0.8 < g-ratio < 1), và giảm số lượng sợi trục bị demyelinated hoàn toàn và đang demyelinating, ở chuột R-EAE được điều trị bằng anti-BMP-2/4, được nghiên cứu bằng kính hiển vi điện tử. Không có tác dụng ức chế miễn dịch đáng kể nào được quan sát trong hệ thần kinh trung ương (CNS) và ngoại vi, trong thời điểm cao điểm của cuộc tấn công đầu tiên hoặc vào cuối thí nghiệm. Hơn nữa, điều trị tĩnh mạch bằng kháng thể anti-BMP-2/4 ở chuột thí nghiệm với cuprizone đã tăng số lượng oligodendrocyte trưởng thành và remyelination trong thể callosum trong giai đoạn phục hồi của bệnh. Dựa trên các phát hiện của chúng tôi, việc khóa đặc hiệu BMP-2/4 có tiềm năng điều trị trong các rối loạn demyelinating như MS, thông qua việc kích thích remyelination trung gian bởi oligodendrogenesis trong các mô bị ảnh hưởng.
Từ khóa
#Oligodendrocyte precursor cells #demyelination #BMP signaling #remyelination #multiple sclerosisTài liệu tham khảo
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