The cross-talk between stem cells and their microenvironment has been shown to have a direct impact on stem cells’ decisions about proliferation, growth, migration, and differentiation. It is well known that stem cells, tissues, organs, and whole organisms change their internal architecture and composition in response to external physical stimuli, thanks to cells’ ability to sense mechanical signals and elicit selected biological functions. Likewise, stem cells play an active role in governing the composition and the architecture of their microenvironment. Is now being documented that, thanks to this dynamic relationship, stemness identity and stem cell functions are maintained. In this work, we review the current knowledge in mechanobiology on stem cells. We start with the description of theoretical basis of mechanobiology, continue with the effects of mechanical cues on stem cells, development, pathology, and regenerative medicine, and emphasize the contribution in the field of the development of ex-vivo mechanobiology modelling and computational tools, which allow for evaluating the role of forces on stem cell biology.

During the last five years, there has been a significantly increasing interest in adult adipose stem cells (ASCs) as a suitable tool for translational medicine applications. The abundant and renewable source of ASCs and the relatively simple procedure for cell isolation are only some of the reasons for this success. Here, we document the advances in the biology and in the innovative biotechnological applications of ASCs. We discuss how the multipotential property boosts ASCs toward mesenchymal and non-mesenchymal differentiation cell lineages and how their character is maintained even if they are combined with gene delivery systems and/or biomaterials, both in vitro and in vivo.

Organoids are a novel three-dimensional stem cells’ culture system that allows the in vitro recapitulation of organs/tissues structure complexity. Pluripotent and adult stem cells are included in a peculiar microenvironment consisting of a supporting structure (an extracellular matrix (ECM)-like component) and a cocktail of soluble bioactive molecules that, together, mimic the stem cell niche organization. It is noteworthy that the balance of all microenvironmental components is the most critical step for obtaining the successful development of an accurate organoid instead of an organoid with heterogeneous morphology, size, and cellular composition. Within this system, mechanical forces exerted on stem cells are collected by cellular proteins and transduced via mechanosensing—mechanotransduction mechanisms in biochemical signaling that dictate the stem cell specification process toward the formation of organoids. This review discusses the role of the environment in organoids formation and focuses on the effect of physical components on the developmental system. The work starts with a biological description of organoids and continues with the relevance of physical forces in the organoid environment formation. In this context, the methods used to generate organoids and some relevant published reports are discussed as examples showing the key role of mechanosensing–mechanotransduction mechanisms in stem cell-derived organoids.

Sequence databases and transcriptome-wide mapping have revealed different reversible and dynamic chemical modifications of the nitrogen bases of RNA molecules. Modifications occur in coding RNAs and noncoding-RNAs post-transcriptionally and they can influence the RNA structure, metabolism, and function. The result is the expansion of the variety of the transcriptome. In fact, depending on the type of modification, RNA molecules enter into a specific program exerting the role of the player or/and the target in biological and pathological processes. Many research groups are exploring the role of RNA modifications (alias epitranscriptome) in cell proliferation, survival, and in more specialized activities. More recently, the role of RNA modifications has been also explored in stem cell biology. Our understanding in this context is still in its infancy. Available evidence addresses the role of RNA modifications in self-renewal, commitment, and differentiation processes of stem cells. In this review, we will focus on five epitranscriptomic marks: N6-methyladenosine, N1-methyladenosine, 5-methylcytosine, Pseudouridine (Ψ) and Adenosine-to-Inosine editing. We will provide insights into the function and the distribution of these chemical modifications in coding RNAs and noncoding-RNAs. Mainly, we will emphasize the role of epitranscriptomic mechanisms in the biology of naïve, primed, embryonic, adult, and cancer stem cells.

The association of lysosomal dysfunction and neurodegeneration has been documented in several neurodegenerative diseases, including Alzheimer’s Disease (AD). Herein, we investigate the association of lysosomal enzymes with AD at different stages of progression of the disease (mild and severe) or with mild cognitive impairment (MCI). We conducted a screening of two classes of lysosomal enzymes: glycohydrolases (β-Hexosaminidase, β-Galctosidase, β-Galactosylcerebrosidase, β-Glucuronidase) and proteases (Cathepsins S, D, B, L) in peripheral blood samples (blood plasma and PBMCs) from mild AD, severe AD, MCI and healthy control subjects. We confirmed the lysosomal dysfunction in severe AD patients and added new findings enhancing the association of abnormal levels of specific lysosomal enzymes with the mild AD or severe AD, and highlighting the difference of AD from MCI. Herein, we showed for the first time the specific alteration of β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC) in MCI patients. It is notable that in above peripheral biological samples the lysosomes are more sensitive to AD cellular metabolic alteration when compared to levels of Aβ-peptide or Tau proteins, similar in both AD groups analyzed. Collectively, our findings support the role of lysosomal enzymes as potential peripheral molecules that vary with the progression of AD, and make them useful for monitoring regenerative medicine approaches for AD.

In this review, we shed light on recent advances regarding the characterization of biochemical pathways of cellular mechanosensing and mechanotransduction with particular attention to their role in neurodegenerative disease pathogenesis. While the mechanistic components of these pathways are mostly uncovered today, the crosstalk between mechanical forces and soluble intracellular signaling is still not fully elucidated. Here, we recapitulate the general concepts of mechanobiology and the mechanisms that govern the mechanosensing and mechanotransduction processes, and we examine the crosstalk between mechanical stimuli and intracellular biochemical response, highlighting their effect on cellular organelles’ homeostasis and dysfunction. In particular, we discuss the current knowledge about the translation of mechanosignaling into biochemical signaling, focusing on those diseases that encompass metabolic accumulation of mutant proteins and have as primary characteristics the formation of pathological intracellular aggregates, such as Alzheimer’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis and Parkinson’s Disease. Overall, recent findings elucidate how mechanosensing and mechanotransduction pathways may be crucial to understand the pathogenic mechanisms underlying neurodegenerative diseases and emphasize the importance of these pathways for identifying potential therapeutic targets.