To combat the obesity epidemic, we will need to develop new biomedical tools more capable of targeting the root cause; namely caloric excess and increased fat deposition. The expansion of beige adipose tissues has been found to be highly effective as a therapeutic for combating metabolic disorders such as obesity in small animal models. To this end, my lab with our collaborators have generated an implantable synthetic organ that can be used clinically to increase the amount of beige adipose tissue in patients. This synthetic organ, termed beige adipose tissue ? matrix assisted cell transplant (BAT-MACT), is built from adipose-derived mesenchymal stem cells (ADMSC) and short peptide adhesion ligand-conjugated hyaluronic acid-based hydrogels optimized to reinforce beige adipocyte differentiation and function. This system has been shown to promote metabolic health and reverse the negative effects of high fat diets. However, the BAT-MACT relies on isolating stem cells from a patient?s white adipose tissues, thus requiring a surgical procedure such as liposuction to collect source material. This proposal outlines steps aimed at streamlining the procedure and reducing the patient burden/costs associated with this therapeutic tool. My goal with this grant is to refine the BAT-MACT into a single injectable by developing a novel biomaterial that will recruit and differentiate the requisite ADMSC populations to generate a functional synthetic organ that is thermogenically active. To accomplish this, my first aim will be to screen a library of extracellular matrix ligands and growth factors know to exert chemoattractive effects on isolated stromal vascular fraction ADMSC using well characterized migration and attachment assays. Components found to promote recruitment and proliferation of preadipocyte populations will be then carried into the second aim which will seek to determine whether the factors identified will promote the desired thermogenically-derived physiological effects, namely increased heat production and lipid metabolism, of the ADMSC in vitro. Optimizations to the hydrogel found to promote recruitment and differentiation will then be applied to animal model systems.
Aim three will explore whether or not these optimized hydrogel networks can be implanted adjacent to adipose depots in vivo and then orchestrate the recruitment and differentiation to promote the development of a synthetic beige adipose tissues, while maintaining minimal recruitment of the host?s immune system. These implants will be examined for their ability to promote metabolic health compared to our previously characterized BAT-MACT technology. This new iteration of bioengineered beige adipose tissue will be titled beige adipose tissue - matrix-assisted in situ implant (BAT-MAISI). This novel bioengineered tissue will be a powerful tool for clinically combating the obesity epidemic and will expand our overall understanding of how to craft and control bioengineered organs for therapeutic purposes.
This project will drastically improve a novel method to generate beige adipose tissue for therapeutic purposes. Specifically, this proposal will develop an implantable biomaterial to promote spontaneous creation of beige adipose tissues adjacent to white adipose tissues without the need to extract and include any cells into the biomaterial ex vivo. Beige adipose tissue expansion has been shown to combat obesity, and this project will produce the simplest way to apply it to patient populations.
