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Viscoelastic cues to induce stem cell migration and neuronal differentiation in cell-free hydrogel-assisted TBI recovery
Introduction
Traumatic brain injury (TBI) is a common neurological trauma caused by external mechanical forces and has high mortality and disability rates; it severely affects people around the world and imposes a serious burden on families, health care and society [1], [2], [3], [4]. After brain trauma, brain tissue is severely damaged, and abundant neurons are lost, this damage, coupled with secondary injuries leading to alterations in cell function and propagation of injury, limits the regeneration of brain tissue and the restoration of neurological function. Traditional treatments for TBI, such as hyperbaric oxygen therapy, noninvasive brain stimulation, and behavioral therapy [5], [6], [7], are less effective in reconstructing damaged neural networks and restoring neural function. Stem cell therapy for TBI has shown favorable results in animal models owing to its ability to replace lost neurons and powerful paracrine effects [8], [9]. However, several challenges, including the low survival rate and uncontrollable differentiation of stem cells in vivo, are faced in the clinical translation of stem cell therapy [10], [11]. In addition, the source of stem cells is limited, and their application often raises ethical issues. The development of tissue-inducing biomaterials offers an alternative strategy for reconstructing biomimetic microenvironments for tissue regeneration without the need for exogenous stem cells; this approach is no doubt more promising for TBI repair. According to the latest consensus on the definition of tissue-inducing biomaterials by scientists worldwide, biomaterials designed to induce the regeneration of damaged or missing tissues or organs without the addition of cells and/or bioactive factors are called tissue-inducing biomaterials [12], [13]. Under the guidance of this concept, in addition to being recognized as bridging grafts, biomaterials also act as the extracellular matrix (ECM) to provide a niche for supporting cell survival and functional expression, thus inducing tissue regeneration. Therefore, ECM cues generated from the physicochemical characteristics of biomaterials play important roles in regulating endogenous stem cell behaviors, including cell migration and differentiation, which are crucial for the regeneration of brain tissue. It is widely accepted that cell migration in three-dimensional (3D) microenvironments plays a critical role in many pathophysiological processes, such as embryonic development, immune cell trafficking, and tissue regeneration [14], [15], [16]. For the repair of TBI with neuronal loss and neural circuit dysfunction, it is also necessary to recruit endogenous stem cells to lesion sites and induce their differentiation toward neurons.
Numerous studies have proven that mechanical cues from ECM affect cellular behavior, including cell migration [17], [18], [19]. The influence of matrix stiffness and elasticity on cell migration has long been reported [20], [21], [22], [23], [24]. One of the famous underlying mechanisms is based on the theory of durotaxis; that is, many cells tend to migrate from softer to stiffer substrates [22]. Although stiff and elastic matrices are widely used for studying cell migration, some soft tissues, such as brain, breast, adipose tissue and muscle, are not perfectly elastic but viscoelastic, which is reflected in the fact that they undergo stress relaxation on time scales of tens to hundreds of seconds when subjected to an external force [25], [26], [27]. Therefore, an increasing number of researchers have focused on the impact of dynamic mechanical microenvironments resulting from the viscoelasticity of matrices on cell behavior, including cell migration [17], [18], [25], [26]. Several studies have revealed that the viscoelasticity of matrices is able to determine cell fate and is thus crucial for tissue regeneration [28], [29], [30]. Given that brain is a typical viscoelastic soft tissue with an extremely low elastic modulus, a biomimetic viscoelastic matrix may have the ability to induce brain tissue regeneration, which is conducive to TBI repair. It is essential to explore the mechanism by which viscoelastic cues from a matrix with a low modulus comparable to that of brain tissue affect the migration and neuronal differentiation of stem cells.
Studies over the past few years have confirmed that the viscoelasticity of microenvironments regulates multiple cellular behaviors that are not observed with conventional elastic matrices, and corresponding mechanotransduction mechanisms have been proposed [17], [26]. The widely held mechanotransduction model for explaining how cells respond to a viscoelastic matrix is the motor–clutch model, in which myosin is regarded as the motor and the nanoadhesion between the cell and the matrix acts as the clutch. Similarly, actomyosin-based contractility coupled to the matrix through integrin-mediated adhesion and integrin-ligand clustering is involved in the mechanotransduction of cells cultured in 3D matrices [18], [22], [25]. All these studies indicate the importance of focal adhesions in cellular mechanotransduction. Originally, Chan and Odde proposed the motor–clutch model to explain the cellular response to stiffness [31]. Using this model, our previous study elucidated, both experimentally and computationally, that a more viscoelastic hydrogel led to larger focal adhesions with longer lifetimes, contributing to the neurite extension of neurons [32]. Recently, Chaudhuri et al. revealed that cells migrate robustly on soft substrates with fast stress relaxation, which was also predicted by computational models of cell migration based on the motor–clutch system [25]. Such regulation on cell migration by viscoelasticity is mediated by filopodia protrusions, rather than lamellipodial protrusions, which are implicated in cell migration on stiff substrates [25]. Moreover, Heilshorn et al. reported that human neural progenitor cells (hNPCs) within more viscoelastic hydrogel exhibited longer neuritic projections and higher expression of genes related to neural maturation [33]. These pioneering works inspired us that viscoelasticity is one of the most important cues of ECM. Recently, a viscoelastic hydrogel consisting of phenylboronic acid grafted hyaluronic acid (HA) and dopamine grafted gelatin was found to be effective in promoting brain lesion healing [34]. However, little is known about the role of a viscoelastic matrix in inducing the migration of stem cells and determining their neuronal differentiation at lesion sites after TBI.
Among all biomaterials, hydrogels have long been preferred in TBI repair due to their ultrahigh water-content, favorable biocompatibility, and tunable mechanical and biochemical properties [35]. Hydrogels derived from natural tissue ECM, such as HA, collagen, fibrin, and gelatin has been widely used to treat TBI [36], [37], [38], [39]. Although these hydrogels can be engineered to mimic the ECM of brain tissue, mimicking the viscoelasticity of brain tissue has usually been ignored. The effect of biomimetic viscoelastic hydrogels on TBI repair remains unclear. Here, to meet the needs of stem cell migration in brain tissue regeneration after injury, we developed a family of composite hydrogels that mimic the structure and mechanical properties of brain tissue. By leveraging a static − dynamic strategy, we decouple the viscoelasticity of hydrogels from other physicochemical properties. The viscoelasticity of hydrogels is tuned over a wide range under the premise that hydrogels have a low modulus comparable to that of brain tissue. We demonstrate that a high viscoelastic hydrogel with fast stress relaxation promotes the migration and neuronal differentiation of stem cells both in vitro and in vivo. Furthermore, we reveal the effectiveness of the biomimetic viscoelastic hydrogel in inducing brain tissue regeneration for TBI repair (Fig. 1)..
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