Regulate Cell Behavior Research Articles

“Young-Mechanical Niche” biomimetic hydrogel promotes dental pulp regeneration through YAP-dependent mechanotransduction

Aging leads to the irreversible deterioration of the extracellular matrix (ECM), compromising cell self-renewal, differentiation, and tissue regeneration. However, the specific mechanisms by which age-related changes in ECM-mediated cell mechanical microenvironment impair regeneration remain elusive. Human dental pulps (hDPs) provide an ideal model to explore this issue due to their accessibility and distinct mechanical properties. In this study, we discovered that young hDPs exhibit higher stiffness and viscoelasticity (i.e., faster stress relaxation time) compared to aged hDPs. Leveraging these findings, we engineered three groups of biomimetic hydrogels recapitulating the native mechanical microenvironment of young and aged hDPs. Our results demonstrated that Y-Gel, which replicates the high stiffness and viscoelasticity of young hDPs, significantly enhances the proliferation and odontogenic differentiation of human dental pulp stem cells (hDPSCs) in vitro and promotes dental pulp regeneration in vivo more effectively than hydrogels mimicking either aged stiffness (AS-Gel) or aged viscoelasticity (AV-Gel) alone. Moreover, YAP-dependent mechanotransduction, particularly through the YAP/TEAD1/CTGF/Cyr61 signaling pathway, plays a critical role in mediating these regenerative effects, with stiffness emerging as a more dominant factor than viscoelasticity. This study provides new insights into the synergistic role of mechanical factors in regulating cell behavior and offers a promising strategy for optimizing mechanical microenvironment to enhance dental pulp regeneration and potentially other tissue regeneration applications, especially from the mechanomedicine perspective.

Integrin Subtypes and Lamellipodia Mediate Spatial Sensing of RGD Ligands during Cell Adhesion.

Understanding how the spatial distribution of adhesive ligands regulates cell behavior is crucial for designing biomaterials. This study investigates how precisely controlled ligand spacing affects cell spreading and integrin subtype engagement. Using engineered polyacrylamide hydrogels with gold nanoparticle arrays, we explored the impact of RGD ligand spacings (30 and 150 nm) on human mesenchymal stromal cells. Cells exhibited distinct morphological behaviors: smaller spacings promoted larger spreading areas, while larger spacings resulted in elongated shapes with reduced spreading. Mechanistically, we found that the α5β1 integrin, not the αvβ3 integrin, played a central role in mediating these responses, alongside lamellipodia formation. Our findings provide critical insights into the spatial sensing of ligands, highlighting the influence of ligand spacing on cellular mechanotransduction and integrin-specific responses. This work advances the understanding of cell-material interactions and offers potential strategies for designing biomaterials to guide cell behavior in tissue engineering.

Nanotechnology-Enhanced Orthopaedic Surgery

Nanomaterials hold significant promise for the future of orthopaedic implants due to their ability to mimic the nanoscale components of the bone, such as collagen fibrils and hydroxyapatite. Nanomaterials can regulate cell behaviour while offering mechanical strength and biocompatibility, making them ideal for bone repair and tissue regeneration. This comprehensive review explores the key existing and potential applications of nanotechnology in orthopaedics, including bone tissue engineering, drug delivery systems, systems combatting implant-related infections, and the surface preparation of implants to enhance osseointegration. These innovations are poised to revolutionise orthopaedic care by improving implant durability, reducing infection risks, and promoting bone regeneration to deliver personalised treatment and create better patient outcomes.

Retraction: Long non-coding RNA SNHG16 regulates cell behaviors through miR-542-3p/HNF4α axis via RAS/RAF/MEK/ERK signaling pathway in pediatric neuroblastoma cells.

Retraction: Long non-coding RNA SNHG16 regulates cell behaviors through miR-542-3p/HNF4α axis via RAS/RAF/MEK/ERK signaling pathway in pediatric neuroblastoma cells.

Understanding the interplay between extracellular matrix topology and tumor-immune interactions: Challenges and opportunities.

Modern cancer management comprises a variety of treatment strategies. Immunotherapy, while successful at treating many cancer subtypes, is often hindered by tumor immune evasion and T cell exhaustion as a result of an immunosuppressive tumor microenvironment (TME). In solid malignancies, the extracellular matrix (ECM) embedded within the TME plays a central role in T cell recognition and cancer growth by providing structural support and regulating cell behavior. Relative to healthy tissues, tumor associated ECM signatures include increased fiber density and alignment. These and other differentiating features contributed to variation in clinically observed tumor-specific ECM configurations, collectively referred to as Tumor-Associated Collagen Signatures (TACS) 1-3. TACS is associated with disease progression and immune evasion. This review explores our current understanding of how ECM geometry influences the behaviors of both immune cells and tumor cells, which in turn impacts treatment efficacy and cancer evolutionary progression. We discuss the effects of ECM remodeling on cancer cells and T cell behavior and review recent in silico models of cancer-immune interactions.

Tuning porosity of macroporous hydrogels enables rapid rates of stress relaxation and promotes cell expansion and migration

Extracellular matrix (ECM) viscoelasticity broadly regulates cell behavior. While hydrogels can approximate the viscoelasticity of native ECM, it remains challenging to recapitulate the rapid stress relaxation observed in many tissues without limiting the mechanical stability of the hydrogel. Here, we develop macroporous alginate hydrogels that have an order of magnitude increase in the rate of stress relaxation as compared to bulk hydrogels. The increased rate of stress relaxation occurs across a wide range of polymer molecular weights (MWs), which enables the use of high MW polymer for improved mechanical stability of the hydrogel. The rate of stress relaxation in macroporous hydrogels depends on the volume fraction of pores and the concentration of bovine serum albumin, which is added to the hydrogels to stabilize the macroporous structure during gelation. Relative to cell spheroids encapsulated in bulk hydrogels, spheroids in macroporous hydrogels have a significantly larger area and smaller circularity because of increased cell migration. A computational model provides a framework for the relationship between the macroporous architecture and morphogenesis of encapsulated spheroids that is consistent with experimental observations. Taken together, these findings elucidate the relationship between macroporous hydrogel architecture and stress relaxation and help to inform the design of macroporous hydrogels for materials-based cell therapies.

Advanced Hydrogels: Enhancing Tissue Bioengineering with RGD Peptides and Carbon Nanomaterials.

The advancement of tissue engineering (TE) is driven by the development of scaffolds that mimic the mechanical, spatial, and biological environment of the extracellular matrix (ECM), crucial for regulating cell behavior and tissue repair. Hydrogels, 3D networks of polymer chains, are particularly suited for TE due to their high biocompatibility, ability to mimic tissue water content, facilitate cell migration, sustain growth factor release, and offer controllable physical properties. However, hydrogels mimicking the ECM often face challenges related to cell adhesion due to the absence of specific receptors. This issue can be addressed by incorporating ECM components into the polymer matrix, such as the peptide sequence arginine-glycine-aspartic acid (RGD), known for its role in cell adhesion. Additionally, carbon nanomaterials (CNMs) offer unique physicochemical properties that can improve scaffold-cell interactions. Despite the potential benefits, there are limited reports on their combination. RGD-CNM hydrogels enable a more accurate emulation of the natural cellular environment, enhancing tissue engineering applications. This hybrid approach may promote robust cell adhesion along with exceptional mechanical and electrical properties. This review outlines the potential benefits of these hybrid scaffolds and their synergistic potential, aiming to inspire new research directions in this innovative field.

Decellularized extracellular matrix derived from dental pulp stem cells promotes gingival fibroblast adhesion and migration

BackgroundDecellularized extracellular matrix (dECM) has been proposed as a useful source of biomimetic materials for regenerative medicine due to its biological properties that regulate cell behaviors. The present study aimed to investigate the influence of decellularized ECM derived from dental pulp stem cells (DPSCs) on gingival fibroblast (GF) cell behaviors. Cells were isolated from dental pulp and gingival tissues. ECM was derived from culturing dental pulp stem cells in growth medium supplemented with ascorbic acid. A bioinformatic database of the extracellular matrix was constructed using Metascape. GFs were reseeded onto dECM, and their adhesion, spreading, and organization were subsequently observed. The migration ability of the cells was determined using a scratch assay. Protein expression was evaluated using immunofluorescence staining.ResultsType 1 collagen and fibronectin were detected on the ECM and dECM derived from DPSCs. Negative phalloidin and nuclei were noted in the dECM. The proteomic database revealed enrichment of several proteins involved in ECM organization, ECM–receptor interaction, and focal adhesion. Compared with those on the controls, the GFs on the dECM exhibited more organized stress fibers. Furthermore, cultured GFs on dECM exhibited significantly enhanced migration and proliferation abilities. Interestingly, GFs seeded on dECM showed upregulation of FN1, ITGB3, and CTNNB1 mRNA levels.ConclusionsECM derived from DSPCs generates a crucial microenvironment for regulating GF adhesion, migration and proliferation. Therefore, decellularized ECM from DPSCs could serve as a matrix for oral tissue repair.

Spatial dimension cues derived from fibrous scaffolds trigger mechanical activation to potentiate the paracrine and regenerative functions of MSCs via the FAK-PI3K/AKT axis

Secretomes from mesenchymal stem cells (MSCs) have significant therapeutic potential and could be the basis for future MSCs treatments. Innovative design of the topology of biomaterials, which mechanically regulate cell behavior and function, can tremendously improve the efficacy of stem cell therapy. However, how spatial dimension cues derived from specific topology command cell mechanotransduction to regulate the paracrine function of MSCs remains unknown. In this study, the three-dimensional (3D) fibrous constructs with box-like pores and precise strand spacing from 150 µm down to only 40 µm were manufactured using melt electrowriting (MEW), which were used to systematically investigate the spatial dimension cues-triggered mechanotransduction of adipose-derived mesenchymal stem cells (Ad-MSCs) and their impact on the paracrine and regeneration function of Ad-MSCs. The results demonstrated that spatial instructions from the 3D fibrous constructs could influence the spatial reorganization of the cytoskeleton, resulting in cell elongation and augmented immunomodulatory and angiogenic paracrine effects of Ad-MSCs, which was most pronounced at a minimum strand spacing of 40 µm. Besides, mechanical activation of the FAK-PI3K/AKT axis significantly enhanced the paracrine function of Ad-MSCs. In vivo experiments demonstrated that the Ad-MSCs trained using well-defined 3D fibrous constructs with a strand spacing of 40 µm significantly promoted skin regeneration via paracrine signals. In conclusion, this study provides a new horizon for deciphering space dimension insights into the interactional mechanisms of mechanotransduction in regulating cell function, which has inspired innovations in biomaterials for improving tissue regeneration. Statement of significanceThis study emphasized that designing cell-scale spatial dimension cues to command mechanical activation via the FAK-PI3K/AKT axis could significantly enhance the paracrine and regenerative functions of Ad-MSCs. Paracrine signals of Ad-MSCs triggered by mechanical activation promoted skin repair and regeneration via the immunomodulation and angiogenesis. The proposed mechanobiological signal transduction triggered by spatial dimensional cues, which potentiates the paracrine and regenerative functions of Ad-MSCs, is a promising engineering strategy and is expected to provide new inspirations for the development of biomaterials based on biophysical signals for cellular behavior modulation.

ContactBlot: Microfluidic Control and Measurement of the Cell-Cell Contact State to Assess Contact-Inhibited ERK Signaling.

Extracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire same-cell measurements of both phenotypic (cell-contact state) and targeted-protein (ERK phosphorylation) profiles, we prepend high-content, whole-cell imaging prior to end-point cellular-resolution Western blot analyses for each of hundreds of individual HeLa cancer cells cultured on that same chip, which we call contactBlot. By indexing the phosphorylation level of ERK in each cell or cell cluster to the imaged cell-contact state, we compare the ERK signaling between isolated and in-contact cells. We observe attenuated (∼2×) ERK signaling in HeLa cells that are in-contact versus isolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells while introducing a multi-omics tool for control and scrutiny of cell-cell interactions.

Fibronectin as a predictor of preeclampsia

Since preeclampsia first emerged a few centuries ago, a substantial portion of humanity has been tormented by this disease, which has jeopardized and disrupted mankind. Numerous biological markers, including ENDOGLIN, PIGF (placental growth factor), SFLT 1(soluble fms like-tyrosine kinase 1), and PAPP-A (pregnancy associated plasma protein-A), suggest preeclampsia. It was beneficial for detecting preeclampsia, even if there was frequent mortality and morbidity among mothers because of the anticipated latency. Then another marker, fibronectin, was added to the picture. A better preeclampsia prognosis leads substantially to an overall decrease in maternal morbidity and mortality. The primary organ that manufactures circulating fibronectin, occasionally referred to as serum fibronectin, is the liver. To enable the extracellular and intracellular matrix to communicate and regulate cell behavior, fibronectin, an extracellular matrix element, primarily interacts with integrin receptors. Fibronectin is a diagnostic marker for a variety of ailments, such as muscular dystrophy, ovarian and stomach cancers, and gestational diabetes. Inflammatory changes result in the release of fibronectin into the bloodstream, and the main triggering factor of preeclampsia is the infiltration of various trophoblasts that injures endothelial tissues and induces inflammation. Therefore, the primary goal of our study was to establish that fibronectin is a biomarker of preeclampsia. To elucidate our perspective and evaluate whether fibronectin is relevant in preeclampsia prediction, we will conduct a qualitative evaluation of prior research and juxtapose it with the findings of the present study. Thus, early detection of preeclampsia could decrease the rate of maternal mortality and morbidity.

Laser-patterning bacterial nanocellulose for cell-controlled interaction

The interfacial topography of biomaterials has been identified as a major biophysical regulator of cell behavior and function, a role played through the interplay with biochemical cues. In this work, we demonstrate the potential of laser as a versatile technology for the direct fine-tuning of the topography of Bacterial nanocellulose (BNC) with bioinspired topographies and micropatterns on a cell size scale. Two lasers were used, with different wavelengths—IR (CO2, 10600 nm) and UV (tripled Nd: YVO4, 355 nm) —attempting to reproduce the Pitcher-plant topography and to create cell-contact guidance patterns, respectively. Different topographies with parallel grooves featuring a 20–300 μm period were generated on the BNC surface with high fidelity and reliability of the generated microstructures, as demonstrated by 3D optical profilometry and scanning electron microscopy. Moreover, it was demonstrated by X-ray photoelectron spectroscopy that laser processing does not result in detectable chemical modification of BNC. The developed anisotropic microstructures can control cell behavior, particularly regarding morphology, alignment, and spatial distribution. Thus, this proof-of-concept study on the high-resolution laser patterning of BNC opens new perspectives for the development of cell-modulating laser-engineered BNC interfaces, scaffolds, and other advanced medical devices, which can potentially broaden the application of BNC in the biomedical field.

Synthetic Materials Used for Cartilage Regeneration in Recent Decade

Cartilage injury is considered the major cause of joint pain, swelling and dysfunction. Due to the cartilage tissue’s limited repair capacity, it’s very urgent and crucial to develop and investigate biomaterials to improve effective cartilage regeneration. Over the past decade, researchers focused of the design and preparation of a variety of synthetic materials. There synthetic scaffolds are expected to provide a favorable cellular microenvironment which is beneficial for cartilage regeneration. This review comprehensively reviews the major synthetic materials that have been recently applied in cartilage regeneration engineering, including a variety of polymers and a number of 3D printed materials. These materials have unique physicochemical structures and properties that can provide biocompatible three-dimensional porous structures, mimic the extracellular matrix environment in vivo, and promotes cell adhesion, proliferation, and differentiation. These properties all guide the orderly regeneration of cartilage tissues. Especially through the composite with bioactive molecules, nanomaterials, etc., these materials can also realize the controlled release of biological signals and precisely regulate cell behavior. In addition, by compositing natural polymers with synthetic polymers gives the hybrid scaffolds good bioactivity, it will also enhance their mechanical properties as well as the scaffold elasticity. These techniques allow researchers to develop the most ideal scaffold that perfectly mimics the natural cartilage environment.

Matrix stiffness increases energy efficiency of endothelial cells

To form blood vessels, endothelial cells rearrange their cytoskeleton, generate traction stresses, migrate, and proliferate, all of which require energy. Despite these energetic costs, stiffening of the extracellular matrix promotes tumor angiogenesis and increases cell contractility. However, the interplay between extracellular matrix, cell contractility, and cellular energetics remains mechanistically unclear. Here, we utilized polyacrylamide substrates with various stiffnesses, a real-time biosensor of ATP, and traction force microscopy to show that endothelial cells exhibit increasing traction forces and energy usage trend as substrate stiffness increases. Inhibition of cytoskeleton reorganization via ROCK inhibition resulted in decreased cellular energy efficiency, and an opposite trend was found when cells were treated with manganese to promote integrin affinity. Altogether, our data reveal a link between matrix stiffness, cell contractility, and cell energetics, suggesting that endothelial cells on stiffer substrates can better convert intracellular energy into cellular traction forces. Given the critical role of cellular metabolism in cell function, our study also suggests that not only energy production but also the efficiency of its use plays a vital role in regulating cell behaviors and may help explain how increased matrix stiffness promotes angiogenesis.

A dual crosslinking strategy to tailor rheological properties of gelatin methacryloyl

3D bioprinting is an emerging technology that enables the fabrication of three-dimensional organised cellular constructs. One of the major challenges in 3D bioprinting is to develop a material to meet the harsh requirements (cell-compatibility, printability, structural stability post-printing and bio-functionality to regulate cell behaviours) suitable for printing. Gelatin methacryloyl (GelMA) has recently emerged as an attractive biomaterial in tissue engineering because it satisfies the requirements of bio-functionality and mechanical tunability. However, poor rheological property such as low viscosity at body temperature inhibits its application in 3D bioprinting. In this work, an enzymatic crosslinking method triggered by Ca2+-independent microbial transglutaminase (MTGase) was introduced to catalyse isopeptide bonds formation between chains of GelMA, which could improve its rheological behaviours, specifically its viscosity. By combining enzymatic crosslinking and photo crosslinking, it is possible to tune the solution viscosity and quickly stabilize the gelatin macromolecules at the same time. The results showed that the enzymatic crosslinking can increase the solution viscosity. Subsequent photo crosslinking could aid in fast stabilization of the structure and make handling easy.

Inferring cellular contractile forces and work using deep morphology traction microscopy

Traction-force microscopy (TFM) has emerged as a widely used standard methodology to measure cell-generated traction forces and determine their role in regulating cell behavior. While TFM platforms have enabled many discoveries, their implementation remains limited due to complex experimental procedures, specialized substrates, and the ill-posed inverse problem whereby low-magnitude high-frequency noise in the displacement field severely contaminates the resulting traction measurements. Here, we introduce deep morphology traction microscopy (DeepMorphoTM), a deep-learning alternative to conventional TFM approaches. DeepMorphoTM first infers cell-induced substrate displacement solely from a sequence of cell shapes and subsequently computes cellular traction forces, thus avoiding the requirement of a specialized fiduciarily marked deformable substrate or force-free reference image. Rather, this technique drastically simplifies the overall experimental methodology, imaging, and analysis needed to conduct cell-contractility measurements. We demonstrate that DeepMorphoTM quantitatively matches conventional TFM results while offering stability against the biological variability in cell contractility for a given cell shape. Without high-frequency noise in the inferred displacement, DeepMorphoTM also resolves the ill-posedness of traction computation, increasing the consistency and accuracy of traction analysis. We demonstrate the accurate extrapolation across several cell types and substrate materials, suggesting robustness of the methodology. Accordingly, we present DeepMorphoTM as a capable yet simpler alternative to conventional TFM for characterizing cellular contractility in two dimensions.

Modulating collagen configuration for flexibly regulating cell adhesion and migration behavior

Cell adhesion and migration behaviors are widely involved in physiological processes, and can be mediated by various factors. Collagen is one representative constituents of extracellular matrix, possessing advantages including excellent biocompatibility, low immunogenicity, and ease to be engineered, which makes collagen be promising biomaterial for regulating cell behaviors. Furthermore, the biofunction of collagen is closely correlated with its configuration. Whereas, current studies on collagen-based biomaterials for regulating cell adhesion and migration are rare, let alone the exploration of the ralationship between the configurations and these two behaviors. (Human umbilical vein endothelial cells, HUVEC) plays significant roles in wounds healing and cancer progression. Therefore, we aimed at disclosing the relationships between the adhesion/migration capability and the collagen origin, structure, and molecular state. In summary, results clearly revealed that denaturation disfavors the adhesion/migration of HUVEC cells, while assembly promotes. The expression levels of F-actin and vinculin, together with the quantity of filopodia were positively correlated with the two processes. Finnaly, our study may provide directions for the further designing of collagen-based biomaterials in the treatment of these kinds of severe diseases.

3D Bioprinting of Artificial Skin Substitute with Improved Mechanical Property and Regulated Cell Behavior through Integrating Patterned Nanofibrous Films.

Three-dimensional (3D) bioprinting has advantages for constructing artificial skin tissues in replicating the structures and functions of native skin. Although many studies have presented improved effect of printing skin substitutes in wound healing, using hydrogel inks to fabricate 3D bioprinting architectures with complicated structures, mimicking mechanical properties, and appropriate cellular environments is still challenging. Inspired by collagen nanofibers withstanding stress and regulating cell behavior, a patterned nanofibrous film was introduced to the printed hydrogel scaffold to fabricate a composite artificial skin substitute (CASS). The artificial dermis was printed using gelatin-hyaluronan hybrid hydrogels containing human dermal fibroblasts with gradient porosity and integrated with patterned nanofibrous films simultaneously, while the artificial epidermis was formed by seeding human keratinocytes upon the dermis. The collagen-mimicking nanofibrous film effectively improved the tensile strength and fracture resistance of the CASS, making it sewable for firm implantation into skin defects. Meanwhile, the patterned nanofibrous film also provided the biological cues to guide cell behavior. Consequently, CASS could effectively accelerate the regeneration of large-area skin defects in mouse and pig models by promoting re-epithelialization and collagen deposition. This research developed an effective strategy to prepare composite bioprinting architectures for enhancing mechanical property and regulating cell behavior, and CASS could be a promising skin substitute for treating large-area skin defects.

Contact Blot: Microfluidic Control and Measurement of Cell-Cell Contact State to Assess Contact-Inhibited ERK Signaling.

Extracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire same-cell measurements of both phenotypic (cell-contact state) and targeted-protein profile (ERK phosphorylation), we prepend high-content, whole-cell imaging prior to endpoint cellular-resolution western blot analyses for each of hundreds of individual HeLa cancer cells cultured on that same chip, which we call contact Blot. By indexing the phosphorylation level of ERK in each cell or cell-cluster to the imaged cell-contact state, we compare ERK signaling between isolated and in-contact cells. We observe attenuated (~2×) ERK signaling in HeLa cells which are in-contact versus isolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells, while introducing a multi omics tool for control and scrutiny of cell-cell interactions.

Molecular Prospective on Malignant Transformation of Mesenchymal Stem Cells: An Issue in Cell Therapy.

Mesenchymal stem cell (MSCs) therapy, as a rapidly developing area of medicine, holds great promise for the treatment of a variety of medical conditions. MSCs are multipotent stem cells that can be isolated from various tissues and could self-renew and differentiate. They secrete cytokines and trophic factors that create a regenerative microenvironment and have immunomodulatory properties. Although clinical trials have been conducted with MSCs in various diseases, concerns regarding the possibility of malignant transformation of these cells have been raised. The studies showed a higher rate of hematological malignancy and carcinogenesis in experimental models after MSC transplantation. The mechanisms underlying malignant transformation of MSCs are complex and not fully understood, but they are believed to involve the presence of special signaling molecules and alterations in cell behavior regulation pathways. Possible pathways that lead to MSCs' oncogenic transformation occur through two mechanisms: spontaneous and stimulated malignant transformation, including cell fusion, fusion proteins, and the tumor microenvironment. MSC-based therapies have the potential to revolutionize medicine, and addressing the issue of malignancy is crucial to ensure their safety and efficacy. Therefore, the purpose of the present review is to summarize the potential mechanisms of the malignant transformation of MSCs. [Figure: see text].