Matrix assisted cell transplantation of brown fat

描述(申请人提供)：棕色脂肪组织(BAT)具有在称为非颤抖生热的过程中以热的形式消耗代谢能量的固有能力，因此可用于新的抗肥胖治疗方法。扩大BAT的策略一般分为两大类，药物/遗传干预以触发内源性BAT分化途径，或体外产生/扩大棕色脂肪然后植入。由于药物激活可能导致白色脂肪组织(WAT)向蝙蝠转变的分化途径，或WAT的“褐变”，存在影响其他组织的分化和功能的风险，并且对WAT的位置和范围控制不佳 BAT扩张，我们将重点放在后一种方法上。在Stahl和Healy实验室的合作中，我们的总体战略将是利用水凝胶生物工程和代谢生物学方面的专业知识来证明基于BAT的抗肥胖策略的可行性，该策略可以很容易地从临床前阶段转化为实际应用。这里的中心假设是，代谢生物学和组织工程的多学科方法可以用来开发一种自体移植方法，以扩大蝙蝠的质量和静息能量消耗，以对抗肥胖相关疾病，如2型糖尿病和肝骨病。我们的方法将集中在：1)利用Wat作为间充质干细胞(MSC)的现成来源，并通过结合可溶性信号因子和优化的黏附配体来优化BAT的分化条件，而不引入转基因；2)开发由生物启发的透明质酸(HYA)水凝胶组成的3D基质，可以促进Wat来源的MSCs向BAT的分化；3)使用经过体外测试的基质进行体内实验，以进一步优化体内性能，重点确定组织持久性、BAT表型的维持、细胞能量学和整个动物的新陈代谢随基质成分、生长因子和植入部位的变化；以及4)证明优化的BAT-MACT确实可以用作一种有效的减肥方法，并促进肥胖相关疾病的保护和逆转。

DESCRIPTION (provided by applicant): Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat in a process termed non-shivering thermogenesis and thus could lend itself to novel anti-obesity treatment approaches. Strategies for expanding BAT fall into two general categories, pharmaceutical/genetic intervention to trigger endogenous BAT differentiation pathways or ex vivo generation/expansion of brown fat followed by implantation. Since pharmacological activation of differentiation pathways that might drive a white adipose tissue (WAT) to BAT transition, or "browning" of WAT, runs the risks of affecting differentiation and function of other tissues and offers poor control of the location and extend of BAT expansion, we will focus on the latter approach. Our overall strategy in this collaboration between the Stahl and Healy labs will be to leverage expertise in bioengineering of hydrogels and in metabolic biology to demonstrate the feasibility of a BAT base anti-obesity strategy that could be readily translated from the pre-clinical stage to actual application. The central hypothesis here is that a multidisciplinary approach of metabolic biology and tissue engineering can be utilized to develop an autologous transplantation approach to expand BAT mass and resting energy expenditure to combat obesity-associated disorders such as type-2 diabetes and hepatosteatosis. Our approach will focus on: 1) utilizing WAT as a readily available source of mesenchymal stem cells (MSC) and to optimize BAT differentiation conditions, without the introduction of transgenes, by combining soluble signaling factors with optimized adhesion ligands; 2) development of 3D matrixes composed of bio-inspired hyaluronic acid (HyA) hydrogels that can be designed to enhance the differentiation of WAT-derived MSCs into BAT; 3) to perform in vivo experiments with matrixes that have been tested ex vivo to further optimize for in vivo performance with a specific focus on determining tissue persistence, maintenance of BAT phenotype, cellular energetics, and whole animal metabolism as a function of matrix composition, growth factors, and implantation site; and 4) to demonstrate that optimized BAT-MACTs can indeed be used as a potent anti-obesity approach and facilitate the protection and reversal of obesity associated disorders.