Method of characterizing and manipulating adipose stem cell depots to a metabolically healthy state
Inventors
Patel, Niketa A. • El Bassit, Ghattas
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-10196612-B1
Publication Date
2019-02-05
Expiration Date
2037-07-11
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Abstract
A method of reprogramming omental adipose cells to a subcutaneous-like lineage is presented herein. The method comprises exposing omental adipose cells to a small molecule such as Basic Fibroblast Growth Factor (bFGF); TRC105; long noncoding RNAs (lncRNAs) MALAT1, GAS5, linc-VLDLR; transcription factors Sox15, Oct4, KLF4, Nanog, Sal4, BMI1; or combinations thereof.
Core Innovation
The invention presents a method of reprogramming omental adipose cells to a subcutaneous-like lineage by exposing them to small molecules such as Basic Fibroblast Growth Factor (bFGF), TRC105, or long noncoding RNAs (lncRNAs) including MALAT1, GAS5, and linc-VLDLR, as well as transcription factors like Sox15, Oct4, KLF4, Nanog, Sal4, BMI1, or combinations thereof. This method aims to alter the metabolic profile of omental adipose cells to resemble that of subcutaneous adipose cells, thus rendering the omental fat metabolically healthier.
The problem being addressed arises from obesity, particularly central obesity characterized by excessive omental (visceral) fat accumulation, which is linked to increased risk of cardiovascular diseases, diabetes, and other comorbidities. There are depot-specific differences in white adipose tissue, with omental fat contributing to metabolic dysfunction, while subcutaneous fat tends to be protective. Obese adipose-derived stem cells (ASCs) from these depots show distinct genetic profiles and altered secretomes, affecting their function and the stem cell niche. Thus, there is a need for methods to manipulate the omental adipose stem cells to a metabolically healthier state resembling subcutaneous adipose tissue.
The inventors characterized ASCs from subcutaneous and omental depots from lean and obese donors and identified specific transcription factors and lncRNAs differentially expressed, as well as depot-specific differences in exosome content. They demonstrated that silencing of protein kinase C delta (PKCδ) affects senescence in ASCs, indicating its role in maintaining the adipose stem cell niche. Furthermore, they showed that the secretome and exosomes from subcutaneous lean ASCs can reprogram obese omental ASCs toward a subcutaneous-like transcription profile. Using these insights, they designed methods employing small molecules and lncRNAs to reprogram omental obese ASCs in vitro, thereby potentially reducing obesity comorbidities by improving metabolic profiles rather than reducing fat quantity.
Claims Coverage
The patent contains two independent claims focusing on methods of altering the metabolic profile of omental obese adipose cells using conditioned medium or exosomes from subcutaneous lean adipose derived stem cells.
Reprogramming omental obese adipose cells using conditioned medium from subcutaneous lean adipose stem cells
A method of altering the metabolic profile of omental obese adipose cells to a subcutaneous lean adipose metabolic profile by exposing them in vitro to conditioned medium derived from cultures of subcutaneous lean adipose derived stem cells. This conditioned medium contains elevated levels of long noncoding RNAs (MALAT1, GAS5, linc-VLDLR) and basic fibroblast growth factor (bFGF). The exposure changes the expression of transcription factors, such as Sox15 and Oct4, in the omental obese adipose cells to resemble that of subcutaneous lean adipose stem cells. The exposure involves 50% v/v conditioned medium for approximately 72 hours.
Reprogramming omental obese adipose cells using exosomes from subcutaneous lean adipose stem cells
A method of altering the metabolic profile of omental obese adipose cells to a subcutaneous lean adipose metabolic profile by exposing them in vitro to exosomes isolated from conditioned media of subcutaneous lean adipose derived stem cells. These exosomes contain elevated levels of long noncoding RNAs (MALAT1, GAS5, linc-VLDLR) and basic fibroblast growth factor (bFGF). Exposure to approximately 10 μg exosomes for about 72 hours changes the expression of transcription factors such as Sox15 and Oct4 in the omental obese adipose cells, inducing a subcutaneous lean adipose stem cell transcription profile.
The independent claims cover methods of reprogramming omental obese adipose cells in vitro by using either conditioned medium or exosomes derived from subcutaneous lean adipose stem cells, leveraging specific molecular contents to alter transcription factor expression and shift metabolic profiles toward a healthier subcutaneous-like state.
Stated Advantages
The method can reduce obesity comorbidities by changing the metabolic profile of omental fat from a disease-promoting to a metabolically healthy state without necessarily reducing fat content.
The approach provides a means to reprogram adipose stem cells to a subcutaneous-like lineage, potentially protecting against the metabolic dysfunctions associated with visceral obesity.
Use of exosomes and conditioned medium enables cell-free therapeutic strategies by leveraging natural intra-cellular messengers for adipose tissue remodeling.
Documented Applications
Treatment of obesity by differentiation of omental adipose cells into a subcutaneous-like phenotype.
Reduction of obesity-related comorbidities such as cardiovascular diseases and diabetes through metabolic profiling of adipose tissue.
Use of adipose-derived stem cells and their secretomes for regenerative medicine and metabolic disease modulation.
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