Tissue-specific transgenic animal models are indispensable research tools for studies on cell types, fundamental functions of cell subsets, their role in health and disease, and potential for therapeutic applications. However, the developing of tissue-specific models is expensive and time-consuming. Our innovation is in application of cell microencapsulation technology for delivery and long-term survival of specific cell subsets in a designated tissue without immune rejection. Intra-abdominal obesity is associated with risks for development of metabolic syndrome, including insulin resistance, chronic inflammation, and impaired wound healing. Increased numbers of adipocytes that can convert fat into heat (thermocytes) in white intra-abdominal fat can reduce obesity, but the number of thermocytes is difficult to control. In a prototypic study, we showed that subset of Aldh1a1-/- preadipocytes (A1KO) with thermogenic characteristics render wild type female mice resistance to intra-abdominal obesity on a high-fat (HF) diet. We implanted (engrafted) subset of microencapsulated A1KO into two intra-abdominal fat depots of wild type female mice on a HF diet. The A1KO preadipocyte subset reduced 23% of lipids in intra-abdominal fat in treated vs. non-treated mice. Importantly, A1KO cells induce also thermogenesis in intra-abdominal fat of host wild-type females by an unknown molecule. However, without specific models, such as ApoE-/-, the contribution of thermocyte subsets to MCM is difficult to assess. Moreover, it is important to find what cell subsets can offset intra-abdominal obesity in male mice and what molecule can effectively induce thermogenesis in intra-abdominal fat. Our results led us to a central hypothesis: Microencapsulated cell engrafts in existing animal models enable identification of cell subset effects on the host tissue, systemic pathogenesis, and discovery of bioactive molecules. This model will be developed in two Specific Aims:
Specific Aim 1. Develop a prototype encapsulation model in ob/ob mice for testing of thermocyte effects on MCM. We expect to show that effective intra-abdominal fat reduction by encapsulated thermocytes in males and/or females will also decrease MCM including glucose tolerance, chronic inflammation, and impaired wound healing genetically obese ob/ob mice.
Specific Aim 2. Utilize encapsulation mouse model for elucidation of paracrine mechanisms we expect to show novel molecules participating in the thermogenic remodeling of intra-abdominal fat using encapsulated model. Significance: The successful completion of this project will provide cost-effective model for study cell subsets in microcapsules for applications in various existing animal models in vivo for biomedical discoveries.
Tissue-specific transgenic animal models are expensive, but necessary tools for studies on fundamental functions of cell subsets for potential therapeutic applications. Our innovation is in application of cell microencapsulation technology for delivery and long- term survival of specific cell subsets in a designated tissue without immune rejection. The successful completion of this project will provide cost-effective model for study cell subsets in microcapsules for applications in various existing animal models in vivo for biomedical discoveries.
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