Engineering the pancreatic niche: Mechanobiological insights into stem cell-derived β-cell therapy for diabetes mellitus

Global burden of diabetes and β-cell failure

Diabetes mellitus (DM) is a highly prevalent and rapidly increasing chronic metabolic disease that currently lacks a curative therapy.^1,2 DM is characterized by increased glucose levels in blood, known as hyperglycemia, which, if left untreated or uncontrolled, often leads to neuropathy, nephropathy, retinopathy, cardiovascular disease, stroke, peripheral vascular disease, and diabetic ulcers, significantly increasing mortality. ³ The global prevalence of DM was approximately 537 million in 2021 and is projected to rise to 643 million in 2030 and 800 million in 2045. ⁴ Worldwide, diabetes has a significant impact on morbidity and mortality. ⁵ Globally, 6.7 million deaths were recorded due to diabetes. The International Diabetes Federation estimates that global healthcare expenditures related to diabetes exceeded $966 billion in recent years, ⁴ highlighting the urgent need for disease-modifying and regenerative strategies that go beyond glycemic control to preserve or restore functional β-cell mass. ⁵

The pancreatic islet as a mechanosensitive microenvironment

The pancreatic islet microenvironment is a highly organized multicellular niche in which endocrine, stromal, vascular, and immune cells cooperate to maintain glucose homeostasis through tightly regulated intercellular signaling.^6,7 This microenvironment comprises pancreatic stellate cells (PSCs), resident macrophages, glucagon-producing α cells, somatostatin-secreting δ cells, and pancreatic polypeptide-secreting cells, in addition to insulin-producing. ⁸ Beyond providing biochemical factors, this microenvironment delivers a spectrum of physical and mechanical cues that are essential for β-cell differentiation, proliferation, survival, maturation, and insulin secretion. Interactions with other endocrine cells, macrophages, endothelial cells, and extracellular matrix (ECM)-derived signals indicate that the islet microenvironment regulates β-cell activity and fate far beyond passive structural support.^9,10 The ECM delivers mechanical and biochemical cues, such as stiffness, viscoelasticity, ligand availability, and topography, which play important roles in maintaining β-cell identity and function, and supporting insulin release. ⁹ In healthy islets, the ECM is soft, with a Young’s modulus of 0.1–1 kPa, contains elevated levels of collagen IV and laminin 411/511, and promotes mechanotransduction through integrins and mechanosensitive ion channels such as Piezo1.^11,12 In obesity and diabetes, the ECM is pathologically remodelled, resulting in increased stiffness (typically ranging from ∼2 to 5 kPa in early fibrotic states to >10 kPa in advanced fibrosis), and the accumulation of advanced glycation end products, which together disrupt β-cell mechanosignaling and promote functional decline.^13,14 Importantly, the reported stiffness values vary depending on species, anatomical region, and measurement modality. The stiffness ranges corresponding to physiological and pathological conditions across different species, anatomical regions, and measurement techniques (including atomic force microscopy and magnetic resonance elastography) are summarized in Table 1, providing a comparative framework for interpreting mechanobiological data. Understanding and actively manipulating the mechanobiological properties of the pancreatic islet microenvironment is therefore central to designing effective stem cell-derived β-cell therapies capable of restoring durable islet function.

OPEN IN VIEWER

Table 1.

Mechanobiological heterogeneity and measurement limitations.

Tissue state	Species	Anatomical region	Stiffness (Young’s Modulus, (E))	Measurement technique	Limitation/note
Healthy	Mouse	Isolated islet	0.1–3.0 kPa	AFM (nanoindentation)	Measures surface mechanics; sensitive to probe size and isolation enzyme digestion time. 12
Healthy	Human	Whole pancreas	1.2 ± 0.2 kPa	MRE (magnetic resonance elastography)	Macro-scale (mm resolution); measures shear stiffness (G), converted to E. 15
Fibrotic/PDAC	Human	Whole pancreas	2.0–5.0 kPa	MRE	Clinical fibrosis typically doubles stiffness compared to healthy controls.16,17
PDAC tumor	Human	Tumor mass	∼4.0–10.0 kPa	AFM	High heterogeneity; local stiff regions (collagen fibers) can exceed 10 kPa. 18
Stiff model	In vitro	Hydrogels	10–25 kPa	Rheology/AFM	Synthetic range often used in biomaterials to mimic extreme fibrosis or tumor stiffness for mechanotransduction assays. 19

β-cell physiology at the interface of metabolism and mechanics

Pancreatic β-cells are key regulators of glucose metabolism and energy homeostasis through their tightly controlled secretion of insulin that controls blood glucose levels. ²⁰ Furthermore, β-cells maintain metabolic balance and promote cell growth. ²¹ Insulin enables glucose uptake by peripheral tissues, particularly skeletal muscle and adipose tissue, where it is stored as glycogen or lipid and utilized for energy metabolism. ²² When insulin action is impaired, persistent hyperglycemia develops, which, if left untreated, contributes to macrovascular complications such as cardiovascular disease and stroke, as well as progressive β-cell stress driven by glucolipotoxicity. Additionally, β-cells respond to incretin hormones, which enhance insulin release after a meal to improve the ability of the body to maintain a normal blood glucose level. ²¹ However, chronic exposure to elevated glucose and sustained secretory demand impose metabolic and mechanical stress on β-cells, ultimately driving β-cell dysfunction characterized by oxidative stress, inflammatory signaling, and impaired insulin secretion. ²³ This progressive β-cell dysfunction is a defining feature of type 2 diabetes mellitus (T2DM). Glucotoxicity and lipotoxicity are major triggers of β-cell apoptosis and dedifferentiation, thereby reducing functional β-cell mass and promoting hyperglycemia.^1,24 Uncontrolled hyperglycemia further exacerbates metabolic dysfunction and long-term macrovascular and microvascular complications. ¹ Lifestyle interventions, including physical activity and weight loss, can partially restore β-cell function in individuals with T2DM, but do not directly address the underlying changes in the mechanical and structural properties of the islet niche. ²⁵

Pancreatic stellate cells and fibrotic remodeling as mechanobiological drivers

Pancreatic stellate cells (PSCs) are specialized mesenchymal cells that constitute approximately 4–7% of the pancreatic parenchymal cell population.^26,27 In their quiescent state, PSCs express nestin and glial fibrillary acidic protein and contain vitamin A–rich lipid droplets.^6,28 They share phenotypic similarities with hepatic stellate cells but exhibit pancreas-specific functional characteristics. ⁶ PSCs have two distinct phenotypes, quiescent and activated. In the quiescent phase, PSCs maintain pancreatic homeostasis by regulating ECM remodeling and supporting the physiological architecture of islets.^26,29 PSCs are activated under pathological conditions such as inflammatory cytokines, hyperglycemia, oxidative stress, or mechanical stress.^7,30 This transformation involves several important changes, including induction of α-smooth muscle actin, loss of vitamin A droplets, increased proliferation and migration, secretion of proinflammatory and profibrotic factors, and enhanced ECM protein synthesis. ²⁹ In diabetic conditions, several factors contribute to PSCs activation within islets. ³⁰ Elevated glucose levels trigger PSC activation by inducing oxidative stress, increasing production of reactive oxygen species (ROS). ⁷ Hypoxia in diabetic islets enhances PSC activation through ROS-mediated mechanisms. ³⁰ Administration of N-acetyl-L-cysteine can attenuate hypoxia-induced PSC activation, confirming the role of oxidative stress. ³⁰ Transforming growth factor- β (TGF-β), mitogen-activated protein kinases (MAPK), platelet-derived growth factor (PDGF), and nuclear factor κB (NF-κB) are major pathways involved in PSC activation. ²⁹ Gene expression profiling has identified Pdpn, Bad, and Fos as critical mediators of diabetes-induced PSC activation, ³¹ linking biochemical and mechanical cues to fibrotic ECM remodeling within the islet niche.

The β-cell microenvironment and emerging concepts in mechanobiology

β-cell function and survival are exquisitely sensitive to their surrounding microenvironment, which comprises the ECM, neighboring endocrine and stromal cells, vascular and immune cells, and soluble mediators. ¹⁰ The ECM of the islet niche is composed of collagen, fibronectin, heparan sulfate, chondroitin sulfate, and laminins, whose composition and organization determine both biochemical ligand presentation and mechanical properties. Mechanical features such as fibrosis, stiffness, and altered viscoelasticity influence β-cell activity by modulating integrin-mediated signaling and growth factor bioavailability.^32,33 Disruption of ECM homeostasis activates mechanical and pro-fibrotic signaling pathways that drive apoptosis, insulin resistance, and progression of diabetes.

Mechanobiology, which investigates how physical and mechanical forces shape cell behavior, has revealed that changes in ECM stiffness, architecture, and tethering can profoundly alter β-cell morphology, polarity, and function. ³⁴ In diabetes, progressive ECM remodeling and altered cell–matrix interactions lead to loss of β-cell identity and gene expression patterns. ¹ Mechanotransduction, including integrin-mediated adhesion, cytoskeletal reorganization, and nucleus–cytoskeleton coupling, converts external forces into biochemical signals that regulate β-cell proliferation, survival, and insulin secretion.^34,35 Central transcription factors such as pancreatic and duodenal homeobox 1 (PDX1) and MafA are influenced by mechanical forces, metabolic inputs, ECM stiffness, and mitochondrial dynamics.^1,36,37 Thus, β-cell health is governed not only by metabolic and inflammatory cues but also by the physical properties and composition of the ECM.^11,33 Pathological ECM remodeling in diabetes and obesity alters tissue stiffness and cell–matrix coupling, thereby impairing β-cell survival and function. ³⁸

Limitations of current β-cell replacement strategies and the mechanobiology gap

Islet transplantation can restore endogenous insulin production but remains constrained by limited donor availability, immune rejection, and progressive loss of graft function.^39,40 Transplanted islets often fail to achieve durable engraftment because they are introduced into an inhospitable microenvironment characterized by hypoxia, inflammation, and aberrant ECM remodeling.^41,42 Stem cell-derived β cells (SC-β cells) generated from pluripotent stem cells and human-derived mesenchymal stem cells provide an alternative, potentially unlimited source of insulin-producing cells. ⁴³ However, SC-β cells often exhibit immature phenotypes and are limited in vivo functionality when transplanted, due to a lack of a supportive microenvironment that replicates the mechanical and biochemical cues of the native islet microenvironment. ⁴⁴ Recent clinical advances underscore both the promise and current limitations of SC-β cell therapy. ViaCyte’s PEC-Direct system demonstrated detectable C-peptide production in vivo, albeit with α-cell predominance, whereas Vertex’s VX-880 therapy significantly reduced HbA1c levels from 8.6% to 6.9% under immunosuppressive treatment (ClinicalTrials.gov: NCT04786262).^45,46 These results validate the therapeutic potential of stem cell-based β-cell replacement but also highlight critical challenges, including incomplete cellular maturation, the need for robust immune protection, and the demanding requirement to manufacture therapeutically relevant cell numbers (on the order of ∼10⁹ cells per patient). Notably, most transplantation strategies have yet to systematically address how fibrotic stiffening, altered viscoelasticity, and disrupted mechanotransduction in the diabetic pancreas limit engraftment and long-term function.

Accumulating evidence indicates that ECM mechanics and mechanotransduction pathways are central regulators of β-cell survival, proliferation, and insulin secretion.^11,47 In diabetic and obese states, pathological ECM remodeling increases stiffness, fibrosis, and viscoelastic changes, which perturb β-cell mechanosensing via mechanosensitive ion channels such as Piezo1 and TRPV4, as well as nuclear effectors including Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ). ⁴⁸ These mechanical perturbations contribute to β-cell dedifferentiation, dysfunction, and apoptosis, representing a previously underappreciated axis of β-cell failure. ⁴⁹ Consequently, engineering biomimetic niches that recapitulate the mechanical properties of healthy islets or actively reverse fibrosis has emerged as a promising strategy to improve SC-β cell maturation, survival, and therapeutic efficacy.^44,50

This review aims to integrate and examine the mechanobiological aspects of the pancreatic microenvironment and their implications for therapies using stem cell-derived β-cells. We compare β-cell function and ECM organization in healthy versus diabetes- and obesity-associated states and delineate how specific alterations in ECM composition, stiffness, and viscoelasticity interfere with β-cell mechanotransduction. We highlight major mechanobiological pathways—including YAP/TAZ, Piezo1, and TRPV4—as potential therapeutic targets. Furthermore, we discuss advanced bioengineering approaches, such as stiffness-gradient hydrogels, patient-derived stem cells, and mechano-pharmacological modulators (including agents such as semaglutide and retatrutide), that aim to mimic or restore physiological pancreatic mechanics. By integrating these concepts, we propose a translational framework for engineering personalized pancreatic microenvironments that support durable β-cell regeneration and function in diabetes.

Structural, cellular, and biomechanical organization of healthy pancreatic islets

The pancreatic islets of Langerhans represent highly organized micro-organs in which spatial architecture, cellular composition, and biomechanical properties are intricately coordinated to maintain glucose homeostasis.^51,52 β-cells typically constitute 60–80% of the islet mass and are surrounded by glucagon-secreting α-cells, somatostatin-releasing δ-cells, pancreatic polypeptide-producing cells, endothelial cells, and stromal components, forming a cohesive endocrine unit that facilitates tightly regulated paracrine communication.^52,53 The islets are richly vascularized, ensuring rapid nutrient and oxygen delivery, which is essential for β-cell function and survival. ⁵⁴ The interaction between endocrine cells and intra-islet capillary network highlights the important role of the microenvironment in maintaining β-cell identity and function.^52,55 The basement membrane-rich ECM, composed predominantly of collagen IV, laminin-411/511, fibronectin, and heparan sulfate proteoglycans, forms a compliant scaffold that actively supports mechanoresponsive signaling rather than serving as a passive structural support.^56,57 Importantly, the healthy islet ECM exhibits a physiologically soft elastic modulus (0.2–1 kPa), generating a viscoelastic niche that buffers mechanical stress while enabling efficient force transmission essential for mechanosensing.^11,15,58 This compliant environment preserves optimal focal adhesion turnover, cytoskeletal organization, and vesicle trafficking required for finely tuned insulin granule exocytosis. ¹¹ The viscoelastic nature of the ECM permits stress relaxation and adaptive deformation, allowing β-cells to respond to fluctuating metabolic and mechanical demands without activating pathological stress responses.^59,60 In this mechanically dynamic niche, β-cells maintain their identity, glucose responsiveness, and survival, underscoring the ECM as a functional regulator of endocrine homeostasis.

Mechanosensing and mechanotransduction in regulation of β-cells functions

β-cells continuously interpret biophysical signals from their surrounding ECM through mechanotransduction pathways that convert mechanical inputs into biochemical and transcriptional responses regulating proliferation, differentiation, and insulin secretion. ⁹ Integrin receptors form focal adhesion complexes linking the ECM to the actin cytoskeleton, enabling β-cells to detect alterations in matrix stiffness, topology, and viscoelasticity.^61,62 This integrin–cytoskeletal network serves as a central mechanosensory interface, transmitting extracellular forces to intracellular signaling cascades including FAK, PI3K–AKT, MAPK, and RhoA/ROCK pathways, which collectively orchestrate cytoskeletal tension and β-cell functional maturation. Mechanosensitive ion channels, particularly Piezo1 and TRPV4, respond to membrane stretch and shear stress by modulating Ca²⁺ influx, thereby directly influencing insulin granule mobilization and secretion.^63–65 Upon activation, these channels couple mechanical deformation to electrical excitability and insulin exocytosis, integrating physical force sensing with metabolic signaling. Ca²⁺ influx further activates downstream regulators, including YAP/TAZ transcriptional coactivators, which shuttle between the cytoplasm and nucleus in response to mechanical stimuli, controlling β-cell proliferation, survival, and phenotypic stability.^9,66–68 Dysregulation of this mechanotransduction axis has been increasingly implicated in β-cell dysfunction and the pathogenesis of diabetes. ⁶⁹

Calcium influx remains the principal trigger for insulin secretion following glucose-stimulated membrane depolarization. Mechanically activated Piezo1 and TRPV4 channels further fine-tune intracellular Ca²⁺ oscillatory dynamics, modulating the amplitude and frequency of Ca²⁺ spikes that govern pulsatile insulin release.^63,69 Under physiological mechanical stress, β-cells exhibit rhythmic Ca²⁺ signaling that facilitates insulin granule docking and exocytosis through SNARE complex activation.^70,71 Healthy ECM mechanics support cytoskeletal dynamics essential for vesicle transport and secretion, whereas pathological matrix stiffening disrupts Ca²⁺ homeostasis, impairs oscillatory signaling fidelity, and ultimately compromises insulin secretory function.^11,72

Type 1 diabetes mellitus

Type 2 diabetes mellitus

PSC-β cell crosstalk and fibrotic islet microenvironment

The interaction between PSC and β-cell is mediated by multiple mechanisms involving direct cell contact and paracrine signaling.^104,105 Activated PSCs release various substances that directly influence the β-cell function and survival. Exposure of β-cells to conditioned media from hypoxia-induced PSCs significantly reduces β-cell survival and increases apoptosis, highlighting the detrimental effects of PSC activation on β-cell health. ³⁰ PSCs enhance β-cell function under certain conditions. Co-culture studies reveal that PSCs from healthy mice promote glucose-stimulated insulin secretion (GSIS) from Min6 cells by secreting IL-6. ¹⁰⁴ A previous study highlighted that Wnt5a plays a significant role in the interaction between PSCs and β-cells. PSCs regulate insulin secretion through Wnt5a-induced calcium signaling and FoxO1-PDX1-GLUT2 pathways, resulting in increased intracellular calcium levels and enhanced pFoxO1, PDX-1, GLUT2, and pCamKII expression in β-cells. ¹⁰⁵

PSC activation leads to excessive accumulation of ECM, resulting in a fibrotic microenvironment that progressively impairs islet function.^7,106 This fibrotic process involves excessive production of collagen I and III, and fibronectin, disrupting normal islet architecture and β-cell interactions. ¹⁰⁷ The fibrotic response creates a self-perpetuating mechanobiological cycle in which increased matrix stiffness further activates PSCs, thereby amplifying tissue remodeling and fibrosis.^108,109 The role of fibrosis in β-cell function is complex, with increased matrix stiffness directly disrupting GSIS through mechanosensitive pathways. ³⁰ Furthermore, fibrotic tissue acts as a diffusion barrier that limits oxygen and nutrient supply to β-cells, increasing cellular stress. ³⁰ Fibrotic remodeling disrupts the vascularization of normal islets and weakens the function and survival of β-cells. ³⁰ Clinical data highlights the important role of pancreatic fibrosis in diabetes progression, where increased fibrosis is associated with a greater risk of developing pancreoprivic diabetes after pancreatectomy, ¹⁰⁶ highlighting the importance of addressing fibrotic mechanisms in the management of diabetes. Therefore, PSCs emerge as central stromal regulators that couple inflammation, hypoxia, and mechanical stress to ECM remodeling, positioning them as key mechanobiological targets in strategies aiming to preserve or restore β-cell function.

β-cell microenvironment and mechanobiological states

The microenvironment of the pancreatic β-cell plays an important role in maintaining its function, proliferation, and survival. This environment is influenced by the composition of ECM and inflammatory cytokines and their interactions with adipocytes.^10,52 Understanding the characteristics of the β-cell dysfunction is essential for comprehending the its microenvironment in different metabolic states, such as obesity and fibrosis, compared to lean and healthy conditions. Previous studies highlighted that the interactions in the β-cell microenvironment affect its physiology and pathophysiology in diabetes. Mechanobiological characteristics of healthy versus obese/fibrotic conditions, including key signaling pathways and ECM changes, are depicted in Figure 1.OPEN IN VIEWER

As illustrated in Figure 1, the healthy β-cell microenvironment is characterized by a compliant, loosely organized ECM composed of a thin basement membrane and sparse collagen fibers, generating a soft mechanical niche (≈0.1–1 kPa). Functional β-cells, surrounded by α-cells, quiescent pancreatic stellate cells (PSCs) containing retinoid droplets, and metabolically normal adipocytes, exhibit robust insulin secretion supported by balanced mechanotransduction. In this state, YAP/TAZ remain predominantly cytoplasmic, Piezo1 and TRPV4 channels finely regulate physiological Ca²⁺ influx, and integrin–FAK complexes maintain stable cell–ECM adhesion and force transmission, collectively preserving cytoskeletal organization, calcium homeostasis, and efficient glucose-stimulated insulin secretion (GSIS).

In contrast, the obese/fibrotic β-cell microenvironment undergoes pathological remodeling marked by ECM stiffening (5–12 kPa), dense collagen bundles, accumulation of advanced glycation end-product (AGE)-mediated crosslinks, increased hyaluronan deposition, and elevated collagen VI expression. β-cells within this environment exhibit pronounced dysfunction, including ER stress, inflammation, and reduced insulin granule density, accompanied by activated PSCs and hypertrophic adipocytes that further amplify fibrosis and inflammatory signaling. Mechanosensors become dysregulated, with aberrant nuclear translocation of YAP/TAZ, pathological Piezo1-mediated Ca²⁺ overload and mislocalization, and hyperactivation of integrin–FAK signaling, collectively driving maladaptive mechanotransduction and transcriptional dysregulation. This mechanically constrained niche establishes a fibrotic feedback loop that exacerbates cellular stress, impairs GSIS, and accelerates diabetes progression.

Beyond mechanical alterations, the ECM also provides essential biochemical cues that influence β-cell behavior. Collagen IV and laminin, produced by pericytes and endothelial cells, are critical for maintaining islet architecture and promoting insulin secretion.^52,110 The dynamic nature of ECM properties allows adaptation to physiological fluctuations; however, during metabolic stress, pro-inflammatory cytokines disrupt these interactions, leading to β-cell dysfunction and apoptosis. ¹⁰ In obesity, chronic inflammation and immune cell infiltration further distort the microenvironment, creating a hostile niche that promotes β-cell death and impaired regenerative capacity. ¹¹¹ Notably, islet macrophages have been reported to exert both inflammatory and regenerative roles under specific contexts, underscoring the complexity and plasticity of the β-cell microenvironment. Collectively, these findings highlight that the β-cell niche exists along a mechanobiological spectrum, where shifts in ECM composition, stiffness, and inflammatory signaling drive the transition from a supportive regenerative environment to a fibrosis-dominated, mechanically hostile state that impairs β-cell survival and function. Understanding this mechanobiological reprogramming is essential for designing therapeutic strategies aimed at restoring functional β-cell mass in diabetes.

Characteristics of the β-cell microenvironment in obese versus lean states

The β-cell microenvironment differs between obese and lean individuals. Obesity is associated with a fibrotic microenvironment characterized by increased ECM deposition, chronic inflammation, and altered mechanical properties. Contrastingly, lean microenvironment exhibits reduced ECM stiffness and inflammatory signaling.^112–114 In obese individuals, ECM deposition increases and becomes stiffer due to the accumulation of collagen and other fibrous proteins, ¹¹² impairing the β-cell function and decreasing insulin secretion by disrupting intracellular signaling pathways, which correlates with reduced β-cell responsiveness to glucose, resulting in impaired insulin release. ¹¹⁵ Additionally, chronic inflammation causes the release of inflammatory cytokines that promote fibrosis and lead to the β-cell apoptosis. ¹¹² Β-cell mass increases in obese individuals compared to that in lean individuals. ¹¹⁶ However, this hyperplasia is often insufficient to overcome insulin resistance over time, leading to a subsequent decline in β-cell mass and function. Additionally, newly formed β-cells may not maintain normal insulin secretion capabilities. ⁹² Contrastingly, the lean individuals exhibit a sufficient ECM composition characterized by optimal levels of fibronectin, collagen, and laminin that support insulin secretion and β-cell adhesion, proliferation, and survival. Additionally, lean individuals have reduced inflammation, which preserves β-cell function and lowers the risk of apoptosis. ¹¹⁴ These observations underscore that ECM composition and mechanics, together with inflammatory status, define distinct mechanobiological states in obese versus lean pancreata, which in turn strongly influence β-cell fate and regenerative capacity. Cellular and vascular changes in the pancreatic niche under healthy and diseased conditions are summarized schematically in Figure 2.OPEN IN VIEWER

Influence of ECM components on β-cell function

ECM is composed of proteins and glycoproteins play a major role in structural support and cellular signaling. Laminin, collagen, fibronectin, and heparan sulfate proteoglycans are the key components of the ECM and influence β-cell function. Each component has major and unique roles in modulating β-cell function. ³³ Collagen provides structural support to the pancreatic islets and influences cellular signaling pathways and promotes β-cell proliferation and survival by binding to integrin receptors on β-cells.^33,117 Laminin, particularly laminin 411 and laminin 511, plays a critical role in β-cell survival and proliferation. It binds with integrin and non-integrin receptors to enhance insulin secretion, promoting β-cell survival and proliferation.^33,52,117 Fibronectin has multiple roles, including adhesion, differentiation, and migration. It binds to integrin receptors on the surface of β-cells, promoting proliferation and enhancing survival.^33,117 The characteristics of the β-cell microenvironment are important for understanding how metabolic dysfunction impacts the health of the pancreas. The difference between obese/fibrotic and lean/soft environments emphasizes how crucial the mechanical properties and composition of the ECM are in regulating β-cell function.

Impact of inflammation, adipokines, and multicellular interactions on β-cells

Inflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ play a significant role in β-cell stress, dysfunction, and apoptosis.^118,119 Exposure to pro-inflammatory cytokines such as IL-1β and IFN-γ induces ER stress, leading to the accumulation of misfolded proteins and altering UPR signaling, triggering apoptosis in β-cells and resulting in β-cell dysfunction, impairing their insulin secretion and production.^118,120 These inflammatory cytokines can alter gene expression in β-cells. Exposure to these pro-inflammatory cytokines can change chromatin structure and activate cis-regulatory elements, leading to β-cell dysfunction. Alteration in the β-cell regulatory landscape is associated with increased to autoimmune attacks in genetically predisposed individuals. ¹¹⁸ Chronic exposure to inflammatory mediators increases β-cell immunogenicity and decreases insulin production, making β-cells more recognizable targets for autoreactive T cells, which leads to their destruction and death during an autoimmune response. ¹²¹

The interaction between adipocytes and islets is complex and plays an important role in metabolic regulation. Adipose tissue secretes adipokines, including adiponectin, leptin, and resistin, which affect β-cell function. Under normal conditions, adiponectin enhances insulin secretion and β-cell survival, while leptin inhibits insulin secretion. ¹²² Adipocytes in obese individuals secrete pro-inflammatory cytokines, which create an inflammatory microenvironment that can cause β-cell stress and lead to β-cell dysfunction. ¹²³ This inflammatory condition is exacerbated by immune cell infiltration into adipose tissue, which leads to impaired insulin resistance and glucose metabolism. ¹²⁴ The interaction between adipose tissue and pancreatic β-cells involves hormonal signaling and other factors, such as the release of FFA from adipocytes. Increased FFA levels can induce lipotoxicity, leading to β-cell apoptosis and decreased insulin secretion. ¹²² Peripancreatic adipose tissue (PAT) is a small fat mass that surrounds the pancreas. PAT plays a role in hepatic steatosis and insulin resistance in obese individuals. ¹²⁵ The communication between pancreatic β-cells and PAT modulates the function of β-cells during metabolic disorders. The interplay between adipokines and cytokines affects the β-cell microenvironment. Chronic inflammation can impair insulin secretion and promote apoptosis due to cellular stress. Additionally, dysregulation of adipokine signaling can lead to β-cell dysfunction by affecting β-cell physiology and through secondary effects due to inflammation. Addressing adipokine dysregulation and inflammation may be crucial for maintaining β-cell function and preventing disease progression. Addressing both adipokine dysregulation and inflammation may therefore be crucial not only for metabolic control but also for preserving a mechanically permissive microenvironment that supports β-cell resilience.

Multicellular interactions in disease progression

The interaction between macrophages and PSCs creates a profibrotic and proinflammatory environment that contributes to the development of diabetes. ²⁸ PSCs secrete high amounts of Th2 cytokines such as IL-4, IL-5, and IL-13, which promote alternative M2 macrophage activation, increasing TGF-β and PDGF expression from M2 macrophages, creating a positive feedback loop that activates more PSCs. ²⁸ Alternatively activated macrophages in the pancreas exhibit increased expression of IL-10, CD206, and TIMP2, and reduced expression of activation markers such as TNF-α. These macrophages increase the expression of matrix metalloproteinase 9, which contributes to ECM remodeling and exhibits immunosuppressive properties that may support diabetes progression. ²⁸ The interaction between macrophages and PSCs is regulated by IL-4 receptor α signaling, as demonstrated by the inability of macrophages lacking IL-4Rα to undergo PSC-mediated alternative activation, suggesting that targeting IL-4/IL-13 signaling pathways may disrupt the pathological interaction between macrophages and PSCs.^28,126

The interaction between α, β-, and δ-cells will be disrupted in diabetes, with PSCs contributing to the modulation of these interactions. Β-cells usually secrete inhibitory factors, including ZN²⁺, γ-aminobutyric acid, and ATP, along with insulin, to regulate α cell function. ⁸ Conversely, glucagon, glucagon-like peptide-1 (GLP-1), and acetylcholine are secreted from α cells to enhance insulin secretion from β-cells through paracrine signaling. ⁸ Previous studies revealed that glucagon binding to its receptors, such as G protein-coupled receptors and GLP-1R, on the surface of β-cells enhances GSIS. ¹²⁷ δ-cells secrete somatostatin, which suppresses insulin and glucagon secretion, serving as a negative feedback mechanism to control hormone release. ⁸

Under diabetic conditions, high glucose and lipotoxicity impair β-cells, reducing insulin secretion and paracrine signals that inhibit α-cells, leading to increased glucagon secretion even under hyperglycemic conditions, aggravating the disease condition. ⁸ The ability of α-cells to enhance β-cells may be diminished due to decreased glucagon secretion or impaired paracrine signaling, further reducing the insulin secretion. Impaired somatostatin secretion or δ-cell dysfunction can worsen hyperglycemia by increasing the glucagon secretion, or cause hypoglycemia by excessively inhibiting α-cell activity, disrupting glucose homeostasis. ¹²⁸ PSC activation disrupts this balance by altering the islet microenvironment and blocking cell-to-cell interactions. The fibrotic ECM secreted by activated PSCs can create a physical barrier between endocrine cells, impairing efficient paracrine signaling. Additionally, PSC-derived inflammatory mediators may influence α- and δ-cell function, disrupting glucose homeostasis.

PSCs interact with pancreatic endothelial cells to regulate the vascularization of islets. ¹²⁶ PSC activation during fibrosis progression results in vascular remodeling, which is characterized by a reduction in capillary density and disrupted vessel architecture. This vascular dysfunction impairs the oxygen and nutrition supply to islets, leading to hypoxia that activates PSCs. ³⁰ The interaction between endothelial cells and PSCs is bidirectional. In diabetes, endothelial dysfunction triggers PSC activation by releasing proinflammatory and profibrotic signaling molecules. Conversely, activated PSCs secrete factors that promote dysregulated angiogenesis and endothelial dysfunction, maintaining the pathological cycle.

These multicellular and matrix-mediated interactions emphasize that diabetes progression is not solely a β-cell–centric process but emerges from coordinated crosstalk among immune cells, stromal cells, vasculature, adipocytes, and endocrine cells within a progressively stiffening and fibrotic ECM. This systems-level mechanobiological view is essential for designing regenerative and stem cell-based interventions that can successfully operate within, or actively remodel, the diseased microenvironment.

Mechanical remodeling of the islet microenvironment in diabetes

Fibrotic remodeling in diabetic β-cells significantly increases tissue stiffness, with elastic moduli ranging from 5 to 20 kPa, and decreases viscosity compared to normal β-cells.^12,129 This shift from a soft, stress-relaxing matrix to a dense, viscoelastically impaired ECM is caused by increased deposition of ECM proteins, including collagen, resulting from obesity-induced inflammation, hyperglycemia, and pro-fibrotic cytokines such as TGF-β.^130–132 Under diabetic conditions, ECM stiffness is increased and viscoelasticity is decreased, reducing the ability of the matrix to dissipate mechanical stress and increasing force transmission to β-cells, which leads to restricted cell deformation, disrupted ECM–β-cell interactions, and impaired mechanotransduction pathways that are important for insulin secretion and β-cell survival.^11,133 These changes promote β-cell dysfunction and apoptosis, increasing T2DM progression and contributing to diabetic retinopathy and nephropathy. ¹ Activated fibroblasts deposit ECM and mediate inflammation, linking classical fibrotic signaling to mechanical dysfunction of the islet niche. ¹³⁴ Understanding these mechanisms is essential for developing therapies that target fibrosis to improve diabetes outcomes.

Pathological stiffening of the islet ECM disrupts the normal function and regulation of mechanosensitive ion channels in β-cells, particularly Piezo1 and TRPV4. Aberrant activation or dysfunction of Piezo1 impairs Ca²⁺ homeostasis and disrupts cellular volume regulation.^11,48 Under hyperglycemic conditions and a stiffer matrix in T2DM, Piezo 1 levels increase abnormally and translocate from the plasma membrane to the nucleus. This mislocalization decouples membrane tension from ion channel activity, impairing membrane excitability and Ca²⁺ influx, which affects insulin secretion. ⁵² Another mechanosensitive channel, TRPV4, which responds to osmotic and mechanical changes, regulates intracellular Ca²⁺ levels and inflammatory pathways.^135–137 Abnormal stiffening of the matrix enhances the interaction between Piezo1 and TRPV4, leading to impaired Ca²⁺ signaling and increased cellular stress, increasing the risk of β-cell dysfunction and apoptosis.^138,139 Simultaneously, increased matrix stiffness activates the mechanosenstive transcriptional co-regulator YAP, resulting in its translocation into the nucleus. ¹⁴⁰ When YAP enters the nucleus, it disrupts normal gene expression, causing β-cells to lose their identity and functional maturity, and to dedifferentiate, which aggravates β-cell failure. ¹⁴¹ Thus, aberrant Piezo1 and TRPV4 signaling together with YAP activation establish a self-reinforcing mechanobiological loop of β-cell dysfunction, dedifferentiation, and apoptosis that drives diabetes progression.

The combined effects of mechanobiological stress and chronic inflammation degrade β-cell health and survival throughout the progression of diabetes. ¹⁴² Mechanical stress caused by ECM stiffening impairs β-cell homeostasis by disrupting Piezo1-mediated ion influx, resulting in abnormal cell swelling or shrinking and reduced cell viability. Abnormal ECM stiffness impairs Ca²⁺ oscillations, which are essential for proper insulin secretion, compromising secretory efficiency at the cellular and tissue levels. ¹⁴³ β-cells initially increase insulin secretion to compensate for insulin resistance; however, sustained secretory demand in a stiff, inflammatory microenvironment leads to β-cell dysfunction, characterized by impaired insulin secretion, dedifferentiation, and loss of β-cell mass.^92,144 Chronic mechanical stress and inflammation further increase β-cell stress by promoting apoptosis and elevating inflammatory cytokine release, which results in fibrosis and additional β-cell death.^145,146 Chronic changes in the mechanical microenvironment caused by ECM remodeling, sustained inflammation, and oxidative stress trigger apoptosis and lead to β-cell dedifferentiation. ¹⁴⁷ The loss of β-cell structure and mass reduces the functional β-cell reservoir, which is essential for glucose regulation, emphasizing the influence of mechanobiology in the development and progression of diabetes. The mechanical characteristics of the β-cell environment can be quantitatively mapped using high-resolution biophysical techniques, including atomic force microscopy (AFM) for nanoscale stiffness measurements,^148,149 Brillouin microscopy for non-invasive profiling of viscoelastic properties, ¹⁵⁰ and traction force microscopy (TFM) for evaluating cell-generated forces and ECM remodeling. ¹⁵¹ While these approaches have substantially advanced our understanding of β-cell mechanobiology, each method presents important limitations that must be considered when interpreting results in a physiological or translational context. Despite the advanced precision of current high-resolution techniques, significant limitations remain when translating findings from in vitro models to in vivo human islet physiology. Although atomic force microscopy (AFM) provides nanoscale resolution, its measurements are restricted to surface mechanics, assessing only the outer layer of islets rather than the internal multicellular architecture. In addition, the contact-based nature of AFM may introduce mechanical artifacts or non-physiological deformation.^149,152 AFM also lacks sufficient temporal resolution to capture rapid mechanotransduction events, such as dynamic insulin secretion.

Similarly, TFM is largely limited to two-dimensional culture systems and therefore fails to recapitulate the complex three-dimensional organization of the islet niche, where cells experience multidirectional forces within a viscoelastic extracellular matrix. ¹⁵³ In vivo, pancreatic β-cells are additionally subjected to mechanical influences such as capillary perfusion, hydrostatic pressure, and neural inputs, which are not adequately modeled in conventional in vitro platforms. ¹⁵⁴

Although AFM and TFM remain valuable tools for mechanistic investigation, their translational relevance is limited. In contrast, Brillouin microscopy has emerged as a promising non-contact approach capable of mapping viscoelastic properties in intact human tissues. Meanwhile, magnetic resonance elastography (MRE) currently represents the only non-invasive technique suitable for in vivo assessment of pancreatic stiffness in clinical settings.^15,155,156 Taken together, these limitations emphasize the need for integrative, multiscale approaches that combine complementary mechanical measurement techniques. Such strategies will be essential for accurately capturing the complex biomechanical landscape of the pancreatic niche and for translating mechanobiological insights into clinically relevant therapeutic strategies.

Mechanical stimuli and β-cell function

Mechanosensitive ion channels in the β-cells, such as PIEZO1, are activated by mechanical forces, leading to Ca²⁺ influx that triggers insulin release. When the PIEZO1 channel is activated, it facilitates glucose-induced insulin secretion by allowing Ca²⁺ influx.^69,157 Mechanical stress and forces can induce deformation of the nucleus, which affects gene transcription related to insulin secretion and production.^158,159 When cells undergo mechanical stress, the force is transmitted to the nucleus through the cytoskeleton, resulting in alterations in its shape and structure. This alteration can activate mechanosensitive transcription factors such as YAP and myocardin-related transcription factor A, allowing them to enter the nucleus and trigger changes in gene expression associated with insulin production. ¹⁶⁰ Mechanical forces trigger chromatin rearrangement, facilitating the entry of transcriptional regulators to DNA and influencing gene expression essential for insulin secretion. Additionally, conditions such as ER stress, worsened by mechanical stressors, can disrupt β-cell activity and insulin secretion by activating signaling pathways such as inositol-requiring enzyme 1α (IRE), activating transcriptional factor, and IRE-JNK signaling pathway, leading to cellular dysfunction. ¹⁴² This mechanism emphasizes the impact of mechanical stimuli on the β-cell structure and function, including insulin release, highlighting the crucial role of mechanotransduction in regulating cellular activities. These mechanical stimuli can also influence metabolic pathways in β-cells. Alterations in ECM stiffness have been linked to dysfunction in glucose metabolism and reduced insulin secretion. By modulating metabolic enzymes such as phosphofructokinase (PFK), mechanical forces can affect insulin secretion dynamics. ⁴⁷ ECM stiffness regulates insulin secretion through PFK activity; however, increased stiffness can lead to insulin dysfunction. ⁴⁷ Thus, mechanical forces profoundly regulate insulin secretion by coordinating nuclear deformation, chromatin accessibility, metabolic signaling, and mechanotransductive pathways. Figure 3 summarizes the integration of soluble and insoluble cues that generate mechanical stimuli, activating integrins, Piezo1, TRPV4, and Hippo signaling pathways to regulate β-cell survival and proliferation.OPEN IN VIEWER

Mechanosensors and signaling pathways in β-cells

β-cells possess diverse mechanosensors, including primary cilia, ion channels, glycocalyx, and integrins, that detect mechanical signals and regulate cellular activity. ⁹ Primary cilia are crucial for detecting mechanical signals and affect the regulation of β-cell activity. ¹⁶¹ Integrins play an important role in mechanosensing by responding to the stiffness of the ECM, which influences the activation and functionality of β-cells. ⁹ Additionally, Piezo1 channels are important ion channels that detect mechanical forces and facilitate the entry of Ca2⁺, which is essential for insulin secretion and the functioning of β-cells. ⁶⁹ When mechanical forces are exerted, these sensors activate various intracellular signaling pathways that contribute to β-cell function. Together, these mechano-receptors form a distributed “sensing network” that couples ECM properties to intracellular biochemical programs and transcriptional outputs. The activation of piezo1 initiates a cascade of intracellular reactions that enhance calcium signaling and electrical activity, both of which are essential for insulin secretion. ⁶⁹ Furthermore, primary cilia and integrins play an important role in mechanotransduction pathways that alter cellular response to mechanical stimuli, affecting the differentiation and proliferation of β-cells.^9,161

Nuclear mechanotransduction, PDX1, chromatin remodeling, and therapeutic targeting

PDX1 is a crucial transcription factor essential for the development, maintenance, and function of pancreatic β-cells responsible for insulin production. ¹⁹⁷ It is indispensable for preserving β-cell identity and transcriptional programs governing insulin biosynthesis and secretion. PDX1 regulates insulin gene expression and participates in early pancreatic morphogenesis, influencing both endocrine and exocrine lineage specification. ¹⁹⁸ Its expression is tightly controlled through multiple signaling networks and cis-regulatory regions; areas I–III coordinate embryonic developmental processes, whereas area IV is key for mature β-cell function and glucose responsiveness. ¹⁹⁹ Dynamic regulation of PDX1 throughout the cell cycle reflects its central role in modulating β-cell proliferation, differentiation, and functional adaptation to environmental stimuli. ²⁰⁰

Mechanical forces propagating from the extracellular matrix through the cytoskeleton induce deformation of the nucleus and reorganization of chromatin architecture, thereby influencing transcriptional accessibility and gene expression.^158,159 These biomechanically induced chromatin alterations regulate the recruitment and activity of transcription factors such as PDX1 at insulin regulatory loci, linking nuclear mechanics to β-cell fate determination. Mechanotransduction-associated mediators, including vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), further modulate PDX1 activity under mechanical stress. ¹⁹⁸ VEGF supports β-cell survival and vascular integrity in mechanically strained environments, while eNOS-derived nitric oxide confers cytoprotective effects during biomechanical challenge.^182,185 Additionally, transient receptor potential (TRP) channels contribute to Ca²⁺-dependent transcriptional modulation by responding to mechanical deformation and integrating mechanosensitive signaling with insulin secretion dynamics.^198,201,202 Collectively, these findings position PDX1 as a central integrator of mechanical, metabolic, and transcriptional governance of β-cell identity.

Importantly, this mechanoregulation of nuclear architecture and transcriptional identity provides a direct foundation for therapeutic intervention. Mechanotransduction pathways are critical regulators of β-cell function and insulin signaling, and their dysregulation contributes directly to the pathogenesis of diabetes. Mechanical stimuli derived from the ECM strongly influence β-cell behavior, and alterations in matrix stiffness significantly impair β-cell proliferation and functional competence. ¹¹⁵ Modulating ECM properties and targeting mechanotransductive signaling cascades therefore offers a strategic avenue to enhance β-cell survival and restore insulin secretory capacity in diabetic conditions. Furthermore, mechanical forces such as shear stress modulate insulin signaling pathways and improve peripheral insulin sensitivity, highlighting the systemic relevance of biomechanical regulation. ¹⁵⁹

Several promising mechanotransduction-based therapeutic targets emerge from this framework. Modulation of YAP/TAZ signaling has been shown to enhance β-cell proliferation and augment insulin secretion, ⁶⁷ while targeting Rho GTPase signaling improves cytoskeletal organization and insulin responsiveness. Stem cell-based strategies further harness these principles to replace dysfunctional β-cells with newly generated insulin-producing cells. Induced pluripotent stem cells (iPSCs) can be differentiated into β-like cells,^203,204 and incorporation of optimized mechanical cues during differentiation significantly improves maturation and functional competence. The integration of mechanotransduction modulation with stem cell therapy thus represents a powerful approach to improve engraftment, survival, and physiological insulin output.

In parallel, several pharmacological agents demonstrate mechanobiology-informed protective effects. Small molecules such as ALK5 inhibitors, harmine, and 5-ludotubercidin promote β-cell proliferation and protect against dedifferentiation by suppressing apoptotic and stress-responsive signaling.^205,206 Antioxidants such as N-acetyl cysteine reduce oxidative damage induced by glucotoxicity and lipotoxicity, preserving β-cell viability and limiting apoptosi. ²⁰⁶ For type 1 diabetes mellitus (T1DM), immunomodulatory strategies aimed at selectively targeting autoreactive T cells, including monoclonal antibody-based interventions, offer protection against autoimmune β-cell destruction while preserving systemic immune competence.^207,208

Finally, enhancement of β-cell function through established pharmacological interventions such as metformin and GLP-1 receptor agonists, combined with lifestyle modifications, remains a cornerstone strategy for diabetes management. Nevertheless, emerging mechanotransduction-centered approaches, particularly when integrated with stem cell-based regenerative therapies, represent a next-generation therapeutic paradigm capable of restoring β-cell identity, functionality, and long-term viability. Advancing this mechanobiology-driven strategy may yield transformative therapeutic platforms for improving glycemic control and clinical outcomes in diabetes.

Role of calcium influx mechanisms in regulating β-cell functions

Stem cell-derived β-cells and the impact of mechanical cues

Strategic engineering of biological microenvironments

Targeting pancreatic stellate cells (PSCs) and fibrosis in mechanobiology-guided therapy

PSCs play an important role in the progression of pancreatic fibrosis and β-cell dysfunction. Targeting their activation and function has therapeutic potential. ⁶ Preclinical studies have demonstrated the efficacy of various approaches, including mechanotransduction regulators, anti-fibrotic agents, and antioxidant therapies. Considering how matrix stiffness contributes to PSC activation and β-cell dysfunction, therapies targeting mechanosensitive pathways may offer novel therapeutic strategies. The use of Piezo1 channel modulators considerably rescues GSIS in stiffer matrix environments. ¹¹

Targeting major fibrotic pathways, such as Hedgehog, TGF-β, and PDGF signaling, can reduce the activation of PSC and ECM deposition.^29,258 In preclinical studies, inhibiting the hedgehog signaling pathway using cyclopamine considerably reduced collagen synthesis, fibroblast proliferation, and myofibroblast differentiation. ²⁵⁸ PSC activation can be suppressed by glutathione through inhibition of the ROS/TGF-β/SMAD signaling cascade. ⁷ Clinical studies have revealed a reduction of glutathione levels in erythrocytes from patients with T2DM, supporting antioxidant therapy. ⁷ Additionally, N-acetyl-cysteine helps protect β-cells from oxidative stress-induced damage and inhibits the activation of PSCs. ³⁰

Technical challenges in differentiating stem cells into functional β-cells

The differentiation of patient-derived stem cells into functional β-cells is complex and not yet fully understood. ¹¹⁹ Despite substantial progress, several challenges hinder the production of mature β-cells, including inefficient differentiation protocols, immature β-cell phenotypes, suboptimal microenvironments, and tumorigenicity risks. Current protocols for differentiating iPSCs and human embryonic stem cells into pancreatic progenitor cells are often inefficient, resulting in a low yield of mature insulin-producing β-cells. ¹¹⁹ Additionally, patient-derived stem cells are ineffective at differentiating into functional β-cells, which may lack proper glucose responsiveness.^262,263

A further challenge lies in maturation: stem cell-derived β-cells may fail to express key markers associated with mature β-cell activity, such as NKX6.1 and MAFA, which are required for appropriate insulin secretion. ²⁶³ The β-cell microenvironment strongly affects the differentiation process, with factors such as growth factors, cell–cell interactions, and ECM composition influencing the efficiency and outcomes of differentiation protocols. Co-culturing pancreatic stromal cells with stem cell-derived progenitors can enhance their maturation into functional β-cells. ²⁶²

Tumorigenicity remains a major concern, as undifferentiated stem cells can form teratomas and tumors if not rigorously removed before transplantation, representing a serious safety risk. ²⁶² Addressing these technical issues related to maturation, differentiation efficiency, and safety is essential for developing effective and clinically viable β-cell replacement therapies.

Integrate mechanobiological platforms for β-cell functional profiling

Recent advances in live-cell imaging and biosensors enable real-time imaging of β-cell volume and membrane tension, which is essential for understanding mechanotransduction. ²⁶⁴ Fluorescent tools such as Flipper-TR and genetically encoded sensors allow visualization of real-time changes in plasma membrane mechanics under physiological and pathological conditions.^265,266 These tools help reveal how mechanical stimuli influence ion channels such as Piezo1, Ca²⁺ influx, and insulin secretion in live β-cells.^9,190

The integration of single-cell transcriptomics, epigenomics, and proteomics with mechanical phenotyping is revolutionizing our understanding of β-cell heterogeneity and mechanobiology.^267,268 Mechano-transcriptomic methods combine cell stiffness measurements using AFM or micropipette aspiration with RNA sequencing to correlate mechanical properties with gene expression profiles.^269,270 This comprehensive strategy has revealed that mechanosensitive pathways, including Piezo1 and YAP/TAZ, play critical roles in β-cell differentiation and dysfunction within diabetic ECM microenvironments.^9,271

High-throughput platforms incorporating stiffness-gradient hydrogels or microfabricated arrays enable systematic screening of pharmacological agents and biomaterials for their effects on β-cell mechanotransduction and function. ⁹ These microarrays expose cells to precisely controlled variations in matrix stiffness and viscoelasticity, allowing analysis of mechanical responses such as Ca²⁺ signaling, YAP nuclear localization, and insulin secretion.^272,273 Such screening systems facilitate rapid identification of optimal mechanopharmacological strategies to enhance the maturation and engraftment of SC-β cells and to design next-generation, mechanobiology-informed therapies for diabetes.