Assessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation

Gouveia, Ricardo M.; Lepert, Guillaume; Gupta, Suneel; Mohan, Rajiv R.; Paterson, Carl; Connon, Che J.

doi:10.1038/s41467-019-09331-6

Cited by 110 publications

(147 citation statements)

References 66 publications

(108 reference statements)

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“…Brillouin microscopy has previously demonstrated non‐disturbing characterization of cellular mechanics. [ 14–18 ] Although the rigorous relationship between high‐frequency longitudinal modulus, characterized by Brillouin technique, and traditional quasi‐static Young's or shear modulus, obtained with contact‐based techniques is not established in soft biological matter, empirically strong correlations have been observed in many physiological and pathologic processes, suggesting the biomechanical changes occurring within cells alter both moduli in the same direction. [ 17,19,20 ] Here, we validated Brillouin measurements for the characterization of nuclear mechanics and used it to directly quantify the changes of longitudinal modulus of the cellular nucleus in response to both epigenetic regulation and cytoskeletal manipulation.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

Zhang

Alisafaei

Nikolić

et al. 2020

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The mechanical properties of the cellular nucleus are extensively studied as they play a critical role in important processes, such as cell migration, gene transcription, and stem cell differentiation. While the mechanical properties of the isolated nucleus have been tested, there is a lack of measurements about the mechanical behavior of the nucleus within intact cells and specifically about the interplay of internal nuclear components with the intracellular microenvironment, because current testing methods are based on contact and only allow studying the nucleus after isolation from a cell or disruption of cytoskeleton. Here, all‐optical Brillouin microscopy and 3D chemomechanical modeling are used to investigate the regulation of nuclear mechanics in physiological conditions. It is observed that the nuclear modulus can be modulated by epigenetic regulation targeting internal nuclear nanostructures such as lamin A/C and chromatin. It is also found that nuclear modulus is strongly regulated by cytoskeletal behavior through a robust mechanism conserved in different culturing conditions. Given the active role of cytoskeletal modulation in nearly all cell functions, this work will enable to reveal highly relevant mechanisms of nuclear mechanical regulations in physiological and pathological conditions.

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Section: Introductionmentioning

confidence: 99%

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

Zhang

Alisafaei

Nikolić

et al. 2020

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“…Targeting ECM mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential [50]. For example, Gouveia et al [51] showed that substrate stiffness within the native limbal epithelial stem cell (LESC) niche is relevant to SC phenotype and wound healing and that treating the fibrotic, burnt surface of the cornea with collagenase restored the mechanical properties of the tissue and its capacity to support LESCs [51].…”

Section: Discussionmentioning

confidence: 99%

Substrate Stiffness Modulates Renal Progenitor Cell Properties via a ROCK-Mediated Mechanotransduction Mechanism

Melica

Regina

Parri

et al. 2019

Cells

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Stem cell (SC)-based tissue engineering and regenerative medicine (RM) approaches may provide alternative therapeutic strategies for the rising number of patients suffering from chronic kidney disease. Embryonic SCs and inducible pluripotent SCs are the most frequently used cell types, but autologous patient-derived renal SCs, such as human CD133+CD24+ renal progenitor cells (RPCs), represent a preferable option. RPCs are of interest also for the RM approaches based on the pharmacological encouragement of in situ regeneration by endogenous SCs. An understanding of the biochemical and biophysical factors that influence RPC behavior is essential for improving their applicability. We investigated how the mechanical properties of the substrate modulate RPC behavior in vitro. We employed collagen I-coated hydrogels with variable stiffness to modulate the mechanical environment of RPCs and found that their morphology, proliferation, migration, and differentiation toward the podocyte lineage were highly dependent on mechanical stiffness. Indeed, a stiff matrix induced cell spreading and focal adhesion assembly trough a Rho kinase (ROCK)-mediated mechanism. Similarly, the proliferative and migratory capacity of RPCs increased as stiffness increased and ROCK inhibition, by either Y27632 or antisense LNA-GapmeRs, abolished these effects. The acquisition of podocyte markers was also modulated, in a narrow range, by the elastic modulus and involved ROCK activity. Our findings may aid in 1) the optimization of RPC culture conditions to favor cell expansion or to induce efficient differentiation with important implication for RPC bioprocessing, and in 2) understanding how alterations of the physical properties of the renal tissue associated with diseases could influenced the regenerative response of RPCs.

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“…1a, b) [1]. The unique paracrine, multicellular and physical properties of the LSC niche signal the LSCs to maintain their stem cell properties [2][3][4]. Reconstructed 3D optical coherence tomography reveals that the limbus architecture comprises a deep and complex network of crypts bordered by the palisades of Vogt (Fig.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Stem Cell Therapy for Limbal Stem Cell Deficiency: A Narrative Review

2020

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Destruction of the limbus and depletion of limbal stem cells (LSCs), the adult progenitors of the corneal epithelium, leads to limbal stem cell deficiency (LSCD). LSCD is a rare, progressive ocular surface disorder which results in conjunctivalisation and neovascularisation of the corneal surface. Many strategies have been used in the treatment of LSCD, the common goal of which is to regenerate a self-renewing, transparent, and uniform epithelium on the corneal surface. The development of these techniques has frequently resulted from collaboration between stem cell translational scientists and ophthalmologists. Direct transplantation of autologous or allogeneic limbal tissue from a healthy donor eye is regarded by many as the technique of choice. Expansion of harvested LSCs in vitro allows smaller biopsies to be taken from the donor eye and is considered safer and more acceptable to patients. This technique may be utilised in unilateral cases (autologous) or bilateral cases (living related donor). Recently developed, simple limbal epithelial transplant (SLET) can be performed with equally small biopsies but does not require in vitro cell culture facilities. In the case of bilateral LSCD, where autologous limbal tissue is not available, autologous oral mucosa epithelium can be expanded in vitro and transplanted to the diseased eye. Data on long-term outcomes (over 5 years of follow-up) for many of these procedures is needed, and it remains unclear how they produce a self-renewing epithelium without recreating the vital stem cell niche. Bioengineering techniques offer the ability to recreate the physical characteristics of the stem cell niche, while induced pluripotent stem cells offer an unlimited supply of autologous LSCs. In vivo confocal microscopy and anterior segment OCT will complement impression cytology in the diagnosis, staging, and follow-up of LSCD. In this review we analyse recent advances in the pathology, diagnosis, and treatment of LSCD.

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Assessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation

Cited by 110 publications

References 66 publications

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

Substrate Stiffness Modulates Renal Progenitor Cell Properties via a ROCK-Mediated Mechanotransduction Mechanism

Recent Advances in Stem Cell Therapy for Limbal Stem Cell Deficiency: A Narrative Review

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