Final Report Summary - METABOSTEM (METABOLIC CONTROL OF IMMATURE STROMAL CELL BIOLOGY)
White adipose tissue (WAT) plays a fundamental role in whole body homeostasis mainly through its role as the main energy store of the organism. WAT shows great plasticity as its mass can vary considerably according to the metabolic and nutritional status of the individual. Its massive enlargement occurring during obesity has motivated a large part of basic and applied research over the last decades as this metabolic disease represents one of the most serious public health problems of the 21st century. The recruitment and proliferation of the adipocytes progenitors, firstly named preadipocytes, represent one of the main cellular mechanisms responsible for WAT development. Among their crucial role in obesity, these cells recently drew the attention of many research labs in the regenerative field and have been renamed ASC (adipose-derived stromal/stem cells). ASC are defined both as multipotent precursors and as supporting cells through their high secretory and immuno-modulatory activity. These ASC hallmarks explain their potent regenerative properties and have prompted numerous clinical studies based on their therapeutic potential. While largely involved in the onset of obesity and intensively studied for their regenerative properties, the intrinsic mechanisms that govern ASC plasticity and fate still remain to be unraveled. The main objective of this METABOSTEM project was to investigate the role of metabolism in the intrinsic biology and fate of ASC. Indeed, a very recent literature claims that metabolism represents a crucial actor in the control of cell physiology that allows proper orientation and fate of immature cells.
The accomplishment of the METABOSTEM project enabled us to demonstrate that metabolism is crucial for ASC fate. In particular, we demonstrated that lactate, a metabolite perceived for a long time as a waste product of glycolytic metabolism, constitutes a key signal in the biology of ASC. Using molecular and pharmacological approaches, we have shown that this metabolite, through changes in the intracellular redox state (NADH,H+/NAD+ ratio), promotes their differentiation into a brown adipocyte phenotype through strong induction of the expression of the mitochondrial uncoupling protein-1 (UCP1). Thanks to the expression of UCP1, brown adipocytes dissipate energy as heat and represent highly oxidative cells. Since the recent (re)-discovery of the presence of UCP1-positive brown adipocytes in human adults, these oxidative cells give rise to real hopes for the therapeutic treatment of metabolic diseases such as type 2 diabetes and obesity. Although various molecular and endocrine factors have recently been shown to activate such cells, our work is the first one to demonstrate that the metabolic environment is crucial for their development. The originality of our results also resides in the new concept that the appearance of brown adipocytes could represent an adaptive mechanism to alleviate a strong redox pressure. We recently published these data (Carrière et al. Diabetes 2014) and wrote two reviews in the field (Carrière et al. Medecine/Science 2014 and Carrière et al. Obesity, under review). The effect of lactate on the biology of ASC is not limited to this pro-differentiating effect. Indeed, we have an article in preparation demonstrating that this metabolite also induces a specific secretion profile in ASC, which could strongly influence the biology of surrounding cells. We also obtained several findings that we will explore in the next future that underpin the importance of metabolism in the biology of ASC.
Realization of this METABOSTEM project enables Audrey Carrière-Pazat i) to obtain original data and get them published, ii) to manage people working with her on the different aspects of the project, iii) to develop several collaborations with national and international teams and iv) to get additional funding. Accomplishment of this METABOSTEM project has scientific breakthroughs in the adult mesenchymal stromal cell field, both in basic and applied research. Indeed, through a better comprehension of ASC intimates properties, our project brings news clues in the understanding of obesity, which is a major issue of public health and could have direct consequences on the way to manipulate and expand ASC for their ultimate and appropriate use in regenerative medicine. Furthermore, we believe that elucidation of the mechanisms that control ASC could serve as a model for the comprehension of mesenchymal stromal cells biology from other tissues, and therefore could bring general new findings for the understanding of maintain of tissue homeostasis and integrity. Accomplishment of this proposal help the host laboratory to contribute to local and European competitiveness in the field of stem cells and metabolic diseases which represent public health diseases whose prevalence is unceasingly increasing and which represent true economical and social burdens.
The accomplishment of the METABOSTEM project enabled us to demonstrate that metabolism is crucial for ASC fate. In particular, we demonstrated that lactate, a metabolite perceived for a long time as a waste product of glycolytic metabolism, constitutes a key signal in the biology of ASC. Using molecular and pharmacological approaches, we have shown that this metabolite, through changes in the intracellular redox state (NADH,H+/NAD+ ratio), promotes their differentiation into a brown adipocyte phenotype through strong induction of the expression of the mitochondrial uncoupling protein-1 (UCP1). Thanks to the expression of UCP1, brown adipocytes dissipate energy as heat and represent highly oxidative cells. Since the recent (re)-discovery of the presence of UCP1-positive brown adipocytes in human adults, these oxidative cells give rise to real hopes for the therapeutic treatment of metabolic diseases such as type 2 diabetes and obesity. Although various molecular and endocrine factors have recently been shown to activate such cells, our work is the first one to demonstrate that the metabolic environment is crucial for their development. The originality of our results also resides in the new concept that the appearance of brown adipocytes could represent an adaptive mechanism to alleviate a strong redox pressure. We recently published these data (Carrière et al. Diabetes 2014) and wrote two reviews in the field (Carrière et al. Medecine/Science 2014 and Carrière et al. Obesity, under review). The effect of lactate on the biology of ASC is not limited to this pro-differentiating effect. Indeed, we have an article in preparation demonstrating that this metabolite also induces a specific secretion profile in ASC, which could strongly influence the biology of surrounding cells. We also obtained several findings that we will explore in the next future that underpin the importance of metabolism in the biology of ASC.
Realization of this METABOSTEM project enables Audrey Carrière-Pazat i) to obtain original data and get them published, ii) to manage people working with her on the different aspects of the project, iii) to develop several collaborations with national and international teams and iv) to get additional funding. Accomplishment of this METABOSTEM project has scientific breakthroughs in the adult mesenchymal stromal cell field, both in basic and applied research. Indeed, through a better comprehension of ASC intimates properties, our project brings news clues in the understanding of obesity, which is a major issue of public health and could have direct consequences on the way to manipulate and expand ASC for their ultimate and appropriate use in regenerative medicine. Furthermore, we believe that elucidation of the mechanisms that control ASC could serve as a model for the comprehension of mesenchymal stromal cells biology from other tissues, and therefore could bring general new findings for the understanding of maintain of tissue homeostasis and integrity. Accomplishment of this proposal help the host laboratory to contribute to local and European competitiveness in the field of stem cells and metabolic diseases which represent public health diseases whose prevalence is unceasingly increasing and which represent true economical and social burdens.