肥大细胞对筋膜脂肪细胞分化和形成的调节作用

Adult adipose-derived stromal vascular cell is thought the progenitor cells responsible for postnatal expansion of existing adipose tissue. However, because these preadipocytes, reside in already existing adipose tissues, they will not govern the formation of a new adipose-tissue at the anatomic site where originally has no fat and thereby no adult adipose-derived progenitor cells. Near recently, we have identified a new type of adipocyte precursor cells abundantly localized within the superficial fascia vasculature between the dermis and skeletal muscles. The fascial preadipocytes express multiple markers of adipogenic progenitors and are highly capable of spontaneous and induced adipogenic differentiation in vitro, and particularly, are physiologically active in vivo. In growing rats, these preadipocytes generate adipocytes dynamically from the fascial adventitia to form a single layer and then multiple layers of primitive adipose lobule, which is believed the rudiment of subcutaneous adipose tissue between the dermis and skeletal muscles, the same locations resided by the superficial fascia. Accordingly, we have proposed a schematic model of the fascia origin of adipose cells, explaining both adipose neogenesis and expansion. Here, we further hypothesize that fascial mast cells may initiate the differentiation and formation of adipose cells in situ the fascia, because the heparin, histamine, 5-hydroxytryptamine, and prostaglandins PGD2 metabolite of 15-deoxy-delta PGJ2 released abundantly from mast cells, are well capable of the induction of adipogenic differentiation. Thus, this study aims to investigate the initial role and the mechanisms by which mast cells activate fascial preadipocyte differentiation. Also, we investigate the effects of mast cells on the neogenesis and expansion of fascial adipose tissue by inducing or inhibiting mast cell degranulation in vivo. We expect that the research achievements of this study are able to ameliorate our new model for the origin of adipocytes from the fascia, which could provide new insights on the histoanatomic knowledge of adipose tissue formation and also might be helpful for seeking a new anti-obesity strategy.

目前认为成体脂肪来源的脂肪干细胞负责脂肪组织增生，但此学说无法解释为何新生脂肪可发生于原本没有脂肪、因而也不会有脂肪源性干细胞的解剖部位。我们最近鉴定了一种新的脂肪干细胞，分布于大鼠皮下与骨骼肌间的浅筋膜组织，生理条件下即呈活跃的自发分化能力，沿浅筋膜微血管网形成脂肪细胞和初级脂肪小叶，即皮下脂肪的雏形。据此我们发表了脂肪起源于筋膜的新模型，解释脂肪新生和扩增。本课题进一步提出，浅筋膜脂肪细胞的新生总是伴有大量肥大细胞的局部聚集，肥大细胞脱颗粒释放大量肝素、组织胺、5-羟色胺和前列腺素PGJ2等活性物质，已知均能显著诱导成脂分化；浅筋膜脂肪细胞分化和形成可被肥大细胞启动。拟以离体试验研究肥大细胞启动筋膜脂肪细胞分化及机制，研究在体激活或抑制肥大细胞脱颗粒对筋膜脂肪形成的影响。通过探究筋膜脂肪新生的生理性始动因素，进一步完善脂肪起源于筋膜模型，拓宽脂肪形成的组织学认识和探索新的肥胖控制策略。

浅筋膜是广泛分布于真皮下层和骨骼肌之间的疏松结缔组织，存在大量具有活跃的自发分化能力的脂肪干细胞。本课题研究表明，筋膜脂肪细胞是一种新的脂肪细胞类型，具有特定的脂肪细胞形态和生理生化反应特征。筋膜脂肪细胞的脂滴较小较碎，存在明显的形态异质性。其基础脂肪分解率高，β3和β1-肾上腺素受体低表达，抵抗儿茶酚胺刺激的脂肪分解，cAMP/PKA活化、perilipin1和HSL表达及磷酸化异常。在受体后途径，对IBMX, Forskolin，db-cAMP刺激的脂肪分解反应仍然正常，提示肾上腺素β3和β1受体低表达是筋膜脂肪细胞对儿茶酚胺激素刺激脂肪分解不敏感的重要原因。脂肪细胞筋膜起源的脂肪生成模型，从逻辑上解释了脂肪新生发生，可发生于原本不存在脂肪组织的解剖部位，而那里肯定不存在脂肪来源性的前脂肪细胞。为研究介导筋膜脂肪分化和生成内源性生理性因素，我们检测到筋膜区域的肥大细胞、脂肪祖细胞和成熟脂肪细胞的空间分布彼此密切相关。肥大细胞释放的大量肝素颗粒分布在筋膜前脂肪细胞周围。大鼠腹膜肥大细胞和RBL-2H3肥大细胞的培养上清液中含有20~30µg/ml的肝素，能有效激活PPAR转录活性，促进关键脂肪生成基因表达，增加筋膜或附睾脂肪源基质细胞的脂肪分化。肥大细胞上清液的脂肪生成作用，可被肝素模拟，但组胺或5-羟色胺无效，并可被硫酸鱼精蛋白拮抗。在大鼠体内局部施用微球包被的肝素可诱导浅筋膜脂肪生成。据此肥大细胞及其颗粒肝素可以作为内源性生理因子，启动和加速浅筋膜脂肪生成。利用浅筋膜组织3D水凝胶中首次构建由单房脂滴脂肪细胞构成的成团的具有典型脂肪组织学结构、具有脂肪细胞甘油三酯合成储存和水解功能的脂肪类器官。浅筋膜组织产生脂肪类器官,有力表明脂肪组织细胞可起源于筋膜。本项目表明，浅筋膜是脂肪细胞的一个新来源，筋膜脂肪是一种具有独特细胞形态和代谢功能特征的脂肪细胞亚群。筋膜上的肥大细胞及其脱颗粒的肝素是启动和加速筋膜脂肪生成的内源性生理因素。课题研究拓宽了对脂肪形成的组织解剖学认识。