Cells and extracellular matrix (ECM) interact to maintain homeostasis and tissue mechanostasis (mechanical homeostasis). Intracellular contractility scales with extracellular stiffness in vivo and in vitro, and cells respond to mild changes in ECM composition and tissue mechanical properties by adequately secreting ECM elements or favoring degradation. Upon pathological changes, cells may engage fibrosis & hypertrophy—producing excessive ECM upon excessive loading—, or apoptosis & atrophy-upon excessive mechanical unloading. Recently, the noninvasive technique magnetic resonance elastography (MRE) showed that brain softening occurs with physiological ageing. Strikingly, individuals with Multiple Sclerosis (MS) present exacerbated softening when compared with age-matched controls, presumably due to deregulated ECM, cell death and consequent loss of mechanostasis. We recently reported that oligodendrocytes (OLs) are mechanosensitive, displaying impaired morphological, differentiation & maturation markers when cultured on substrates with excessive or insufficient stiffness, comparing with brain compliant matrices. We propose that ECM remodeling/degeneration & cell death occurring in MS cause deregulation of cell-ECM mechanostasis and consequent functional impairment, promoting disease progression. The brain ECM is highly complex, hence unsuitable for direct therapy on its multiple deregulated components. Instead, we propose using soluble modulators of key proteins involved in intracellular contractility, to mimic physiological stiffness in a deregulated-ECM context, putatively achieving (i) enhanced OL survival and function, and (ii) normalized production of ECM components by distinct cell types. We aim to tackle the implications of brain softening in MS and test innovative ideas that will open new avenues for future therapeutic intervention. We will unveil mechanisms underlying mechanomodulation of OL differentiation & survival in a context of intracellular contractility, and test several soluble modulators of mechanotransduction using our in vitro setup, aiming to mitigate the negative effects of excessive softness on oligodendrocytes. An observational longitudinal study will be conducted with MS patients. Brain stiffness will be assessed by MRE (complemented with clinical assessment) during routine magnetic resonance performed immediately before engaging treatment with a relevant second-line disease modifying agent (DMA), being the first-line DMA (dimethyl fumarate)-treated patients the clinical control group.
The main goals of the project are i) to understand the impact and underlying mechanisms of mechanobiology in oligodendrocytes and ii) its implication in multiple sclerosis (MS). The project ultimately aims to identify novel therapeutic avenues for MS.
Rui Manuel Dias Cortesão dos Santos Bernardes (CO-PI)
Ana Carolina Santo Mendes
Ana Catarina Rodrigues Cardoso
Ana Luisa Mendanha Falcão
Ana Margarida Flores Ferreira Novo
Francisco Jose Santiago Fernandes Amado Caramelo
Gabriel Nascimento Ferreira da Costa
Gonçalo de Sá e Sousa de Castelo Branco
João Valente Duarte
Livia Maria de Abreu Freire Diogo Sousa
Miguel de Sá e Sousa de Castelo-Branco
Pedro Miguel Picado de Carvalho Serranho
Ricardo Filipe Alves Martins
Sónia Raquel Marques Batista