Biology subjects

Havis, E.

Publications and source records attributed to Havis, E..

4 recordsLinked to original sources

bioRxiv2024

Human adipose stromal cells differentiate towards a tendon phenotype with extracellular matrix production and adapted visco-elastic properties in a 3D-culture system

Tendon cell differentiation relies on molecular and mechanical parameters that control the expression of tendon-associated transcription factors and extracellular matrix proteins. However, the minimal cues able to initiate tendon differentiation from progenitor cells remains unknown. We analysed the tendon differentiation program in human adipose stromal cells (hASCs) cultured in a minimal 3D-system. We generated 3D-hASC constructs by embedding hASCs in a type-I collagen gel under a static uniaxial geometrical constraint with no additional molecular and mechanical cues, and assessed tendon-associated gene expression and mechanical properties for up to three weeks in culture. Analysis of tendon-associated genes revealed a molecular progression consistent with the acquisition of a tendon phenotype. The analysis of viscoelastic properties of 3D-hASC constructs by nano-indentation indicated a progressive increase in tissue stiffness up to 10 kPa, concomitant with a reduced stress relaxation indicative of solid-like mechanical properties. These changes in mechanical properties parallel the molecular change of matrix genes during the time of cultures. In summary, we have established that hASCs cultured in a minimal 3D-system progress into the tendon differentiation program associated with variations of mechanical properties.

developmental biology↗

bioRxiv2020

Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

Exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

developmental biology↗

bioRxiv2020

NOTCH inhibition promotes myoblast fusion by releasing HEYL repression on TMEM8C regulatory regions in foetal skeletal muscles

Differentiation and fusion are two intricate processes involved in skeletal muscle development. The close association of differentiation and fusion makes it difficult to address the process of fusion independently of differentiation. Using the fusion marker myomaker, named TMEM8C in chicken, we found that both TMEM8C transcripts and the differentiated and fusion-competent MYOG+ cells are preferentially regionalized in the central regions of limb foetal muscles in chicken embryos. Because the NOTCH signalling pathway is a potent inhibitor of muscle differentiation during developmental myogenesis, NOTCH function in myoblast fusion was not addressed so far. We analysed the consequences of NOTCH inhibition for myoblast fusion and TMEM8C expression during foetal myogenesis using in vitro and in vivo chicken systems. NOTCH inhibition following chicken embryo immobilisation or in myoblast cultures increased TMEM8C expression and myoblast fusion. Moreover, we showed that NOTCH inhibition induced the un-binding of the HEYL transcriptional repressor from the TMEM8C regulatory regions in limb muscles and myoblast cultures. These results identify a molecular mechanism underlying the fusion-promoting effect of NOTCH-inhibition during foetal myogenesis.

developmental biology↗

bioRxiv2017

Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice

Beige adipocyte differentiation within white adipose tissue, referred to as browning, is seen as a possible mechanism for increasing energy expenditure. The molecular regulation underlying the thermogenic browning process has not been entirely elucidated. Here, we identify the zinc finger transcription factor EGR1 as a negative regulator of the beige fat program. Loss of Egr1 in mice promotes browning in the absence of external stimulation and activates Ucp1 that encodes the key thermogenic mitochondrial uncoupling protein-1. Moreover, EGR1 is recruited to the proximal region of the Ucp1 promoter in subcutaneous inguinal white adipose tissue. Transcriptomic analysis of subcutaneous inguinal white adipose tissue in the absence of Egr1 identifies the molecular signature of white adipocyte browning downstream of Egr1 deletion and highlights a concomitant increase of beige differentiation marker and decrease in extracellular matrix gene expression. Conversely, Egr1 overexpression in mesenchymal stem cells decreases beige adipocyte differentiation, while increasing extracellular matrix production. These results uncover the role of Egr1 in blocking energy expenditure via direct Ucp1 transcription regulation and highlight Egr1 as a therapeutic target for counteracting obesity.

developmental biology↗