Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, PelizaeusMerzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.

2020) MiR155-5p in adventitial fibroblastsderived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing ABSTRACT Proliferation of vascular smooth muscle cells (VSMCs) plays crucial roles in vascular remodelling and stiffening in hypertension. Vascular adventitial fibroblasts are a key regulator of vascular wall function and structure. This study is designed to investigate the roles of adventitial fibroblasts-derived extracellular vesicles (EVs) in VSMC proliferation and vascular remodelling in normotensive Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR), an animal model of human essential hypertension. EVs were isolated from aortic adventitial fibroblasts of WKY (WKY-EVs) and SHR (SHR-EVs). Compared with WKY-EVs, miR155-5p content was reduced, while angiotensin-converting enzyme (ACE) content was increased in SHR-EVs. WKY-EVs inhibited VSMC proliferation of SHR, which was prevented by miR155-5p inhibitor. SHR-EVs promoted VSMC proliferation of both strains, which was enhanced by miR155-5p inhibitor, but abolished by captopril or losartan. Dual luciferase reporter assay showed that ACE was a target gene of miR155-5p. MiR155-5p mimic or overexpression inhibited VSMC proliferation and ACE upregulation of SHR. WKY-EVs reduced ACE mRNA and protein expressions while SHR-EVs only increased ACE protein level in VSMCs of both strains. However, the SHR-EVs-derived from the ACE knockdown-treated adventitial fibroblasts lost the roles in promoting VSMC proliferation and ACE upregulation. Systemic miR155-5p overexpression reduced vascular ACE, angiotensin II and proliferating cell nuclear antigen levels, and attenuated hypertension and vascular remodelling in SHR. Repetitive intravenous injection of SHR-EVs increased blood pressure and vascular ACE contents, and promoted vascular remodelling in both strains, while WKY-EVs reduced vascular ACE contents and attenuated hypertension and vascular remodelling in SHR. We concluded that WKY-EVs-mediated miR155-5p transfer attenuates VSMC proliferation and vascular remodelling in SHR via suppressing ACE expression, while SHR-EVs-mediated ACE transfer promotes VSMC proliferation and vascular remodelling. ARTICLE HISTORY

Mesenchymal stem cells (MSCs IntroductionMesenchymal stem cells (MSCs) are defined as a group of multipotent stem cells that can functionally differentiate into at least bone, fat, and cartilage in vitro and in vivo. [1][2][3][4][5][6][7][8] Under appropriate culture conditions, MSCs are readily amplified in vitro for several passages without signs of senescence and differentiation. The 2 properties render them as an intriguing source in cell therapy and tissue engineering. MSCs were first documented by Friedenstein et al at an extremely low frequency within the bone marrow (BM), a canonical reservoir for a variety of stem cells. 1 Functionally, the self-renewal and differentiation of hematopoietic stem cells (HSCs) are tightly and precisely regulated by the marrow stromal milieu, a complex cellular network composed of the descendents of MSCs. For example, osteoblasts lining the bone surface can modulate the HSC expansion via Notch signaling pathway or N-cadherin/␤-catenin adherens complex in vitro and in vivo. 9,10 The MSC, itself, can also modulate hematopoiesis in vitro through secreting a set of hematopoietic cytokines and intercellular contact. 11,12 Systemic administration of adult or fetal tissue-derived MSCs promotes the homing and engraftment of HSCs in vivo by unknown mechanisms. [13][14][15][16] Despite of our increasing understanding of MSCs in adult hematopoiesis, little is known about their developmental origin and correlation with strikingly changing blood-forming sites during embryogenesis, particularly in the human being. 17 The first wave of hematopoiesis in humans is initiated during the third week in the extraembryonic yolk sac (YS), characterized by the production of nucleated erythrocytes in situ. 18,19 As is the case in other higher vertebrates, the second wave is characterized by de novo generation of HSCs in the intraembryonic P-Sp/AGM, followed by migration and colonizing downstream fetal liver for further maturation and amplification. [20][21][22][23] Campagnoli et al claim that human MSCs appear first in fetal blood at the seventh week, and later in the fetal liver and bone marrow from the 10th week. 24 Recently, Mendes et al reported that the mesenchymal progenitors are exclusively allocated in the mouse AGM. 25 However, the ontogeny of human MSCs in the embryonic hematopoietic tissues remains unknown.Herein, we found that human AGM region served as a potent niche for embryonic MSCs that were roughly identical to the bone marrow regarding general morphology, immunophenotype, triple differentiation capacity, and immunobiologic feature. The expression of pluripotential-related markers (Oct-4 and Nanog) and the hematopoietic supportive activity in AGM-derived MSCs corroborated their development stage and anatomic location. Methods Human samplesEighteen human embryos at 25 to 40 days of development were obtained immediately after voluntary terminations of pregnancy induced with the RU 486 antiprogestative compound. Human tissue collection for research purpose was approved by Research Eth...

Background/Aims: Angiotensin (Ang) II plays vital roles in vascular inflammation and remodeling in hypertension. Phenotypic transformation of vascular smooth muscle cells (VSMCs) is a major initiating factor for vascular remodeling. The present study was designed to determine the roles of NLRP3 inflammasome activation in Ang II-induced VSMC phenotypic transformation and vascular remodeling in hypertension. Methods: Primary VSMCs from the aorta of NLRP3 knockout (NLRP3^-/-) mice and wild-type (WT) mice were treated with Ang II for 24 h. Subcutaneous infusion of Ang II via osmotic minipump for 2 weeks was used to induce vascular remodeling and hypertension in WT and NLRP3^-/- mice. Results: NLRP3 gene deletion attenuates Ang II-induced NLRP3 inflammasome activation, phenotypic transformation from a contractile phenotype to a synthetic phenotype and proliferation in primary mice VSMCs. Ang II-induced hypertension and vascular remodeling in WT mice were attenuated in NLRP3^-/- mice. Furthermore, Ang II-induced NLRP3 inflammasome activation, phenotypic transformation and proliferating cell nuclear antigen (PCNA) upregulation were inhibited in the media of aorta of NLRP3^-/- mice. Conclusions: NLRP3 inflammasome activation contributes to Ang II-induced VSMC phenotypic transformation and proliferation as well as vascular remodeling and hypertension.