• Altered calcium accumulation
• And Topo-2β expression
• BG01V human embryonic stem cells
• Metabolic activity
• Morphology
• Neuronal differentiation
• Senescence

• Biophysical cues
• Chromatin modification
• Electrical stimulation
• Intracellular calcium
• Tissue repair

• Chromatin/metabolism
• Calcium/metabolism
• Humans
• Cytosol/metabolism
• Ion Channels/metabolism
• Cell Nucleus/metabolism
• Electric Stimulation
• Cell Proliferation
• Cell Movement
• Animals
• Actomyosin/metabolism

• Electroactive microcarrier
• Magnetic microcarrier
• Stimuli-responsiveness
• Tissue repair

• Aurora A
• calcium
• optogenetics
• primary cilia
• store-operated Ca2+ entry

• Calcium Signaling/physiology
• Calcium Channels/genetics
• Calcium Channels/metabolism
• Calcium/metabolism
• Aurora Kinase A/genetics
• Aurora Kinase A/metabolism
• Endoplasmic Reticulum/metabolism

• 112-2740-B-006-002 Ministry of Science and Technology, Taiwan
• 112-2314-B-006-076 Ministry of Science and Technology, Taiwan

• Electrical stimulation
• In-house devices
• Mesenchymal stem cells
• Polypyrrole

• Polymers/chemistry
• Pyrroles/pharmacology
• Pyrroles/chemistry
• Cell Line
• Electric Stimulation

• Tissue engineering
• mesenchymal stem cells
• multipotency
• regenerative dentistry
• stemness
• tissue regeneration

• Humans
• Dental Pulp/metabolism
• Tissue Engineering
• Stem Cells/physiology
• Tooth
• Dentistry

• R01 DE021139 NIDCR NIH HHS
• R01 DE021410 NIDCR NIH HHS
• R37 DE021410 NIDCR NIH HHS

• Cell elongation
• Cytoskeleton orientation
• Mesenchymal stem cells
• Osteogenesis
• Proliferation
• Volta potential pattern

• Humans
• Mesenchymal Stem Cells/metabolism
• Osteogenesis
• Bone and Bones
• Cytoskeleton/metabolism
• Actin Cytoskeleton

• Calcium oscillations
• Differentiation
• Metabolism
• Osteoblasts

• Calcium Signaling
• Calcium/metabolism
• AMP-Activated Protein Kinases/metabolism
• AMP-Activated Protein Kinases/pharmacology
• Cell Differentiation
• Osteoblasts/metabolism
• Adenosine Triphosphate/metabolism

• No. 11872297 National Natural Science Foundation of China
• No. 31670954 National Natural Science Foundation of China

• Ca2+ oscillations
• Orai1
• STIM1
• arrhythmogenic cardiomyopathy
• cardiac mesenchymal stromal cells
• fibro-adipogenic differentiation
• flecainide
• store-operated Ca2+ entry

• Grant Agreement N. 828984, LION-HEARTED EU Horizon 2020 FETOPEN-2018-2020 Program
• Dipartimenti di Eccellenza Program (2018-2022) - Dept. of Biology and Biotechnology "L. Spallanzani" Italian Ministry of Education, University and Research (MIUR)
• Fondo Ricerca Giovani University of Pavia
• Identification Number: CVU121216 Consejo Nacional de Ciencia y Tecnología

• Tissue Scaffolds/chemistry
• Biomimetics
• Osteogenesis
• Bone Regeneration
• Cell Differentiation
• Printing, Three-Dimensional
• Tissue Engineering

• Natural Science Foundation of Beijing Municipality
• State Key Laboratory of New Ceramic and Fine Processing Tsinghua University
• Tsinghua University Peking Union Medical College Hospital Initiative Scientific Research Program

• Arrhythmogenic cardiomyopathy
• CaMKII
• Calcium signalling
• Cardiac mesenchymal stromal cells
• Flecainide
• Store-operated Ca2+ entry

• Mice
• Animals
• Humans
• Flecainide
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Myocytes, Cardiac
• Calcium
• Mesenchymal Stem Cells
• Cardiomyopathies/genetics

• Italian Ministry of Health
• Fondazione di Comunità Milano e Fondo Fondazione Giacomo Ponzone
• H2020 Future and Emerging Technologies
• Italian Ministry of Education

• Aspartame
• Beta-cell differentiation
• Glucose metabolism
• Metformin
• Mitochondrial remodeling
• Pancreatic progenitor cells

• Conductive materials
• Electrical stimulation
• Mesenchymal stem cells
• Osteogenic differentiation
• Piezoelectricity
• Signaling pathways

• Cell Differentiation/physiology
• Cues
• Electric Stimulation
• Mesenchymal Stem Cells
• Osteogenesis/physiology

• Conjunctiva Mesenchymal Stem Cells (CJMSCs)
• differentiation
• electrical induction
• miR-9 overexpression
• photoreceptor-like cells

• alternating current (AC)
• alternating electromagnetic field (EMF)
• chondrogenic differentiation
• mesenchymal stem progenitor cells (MSPCs)
• osteogenic differentiation

The induction and direction of stem cell differentiation into needed cell phenotypes is the central pillar of tissue engineering for repairing damaged tissues or organs. Conventionally, a special recipe of chemical factors is formulated to achieve this purpose for each specific target cell type. In this work, it is demonstrated that the combination of extrinsic photobiomodulation and collagen-covered microislands could be used to induce differentiation of Wharton’s jelly mesenchymal stem cells (WJ-MSCs) with the differentiation direction dictated by the specific island topography without use of chemical factors. Both neurogenic differentiation and adipogenic differentiation could be attained with a rate surpassing that using chemical factors. Application of this method to other cell types is possible by utilizing microislands with a pattern tailored particularly for each specific cell type, rendering it a versatile modality for initiating and guiding stem cell differentiation.

• Bone marrow mesenchymal cells
• light therapy
• low-level laser therapy
• mesenchymal stem cell

• CRAC channel
• calcium signaling
• ion channels
• light-sensitive Ca2+ permeable channels
• opsins
• optogenetics

• Animals
• Calcium/metabolism
• Calcium Signaling
• Disease
• Humans
• Ion Channels/metabolism
• Optics and Photonics
• Optogenetics

• P 30567 Austrian Science Fund FWF
• P 32851 Austrian Science Fund FWF
• R01 GM129325 NIGMS NIH HHS
• W 1250 Austrian Science Fund FWF

Adipose-derived mesenchymal stromal cells (ASCs) are multipotent stem cells which can differentiate into various cell types, including osteocytes and adipocytes. Due to their ease of harvesting, multipotency, and low tumorigenicity, they are a prime candidate for the development of novel interventional approaches in regenerative medicine. ASCs exhibit slow, spontaneous Ca²⁺ oscillations and the manipulation of Ca²⁺ signalling via electrical stimulation was proposed as a potential route for promoting their differentiation in vivo. However, the effects of differentiation-inducing treatments on spontaneous Ca²⁺ oscillations in ASCs are not yet fully characterised. In this study, we used 2-photon live Ca²⁺ imaging to assess the fraction of cells showing spontaneous oscillations and the frequency of the oscillation (measured as interpeak interval—IPI) in ASCs undergoing osteogenic or adipogenic differentiation, using undifferentiated ASCs as controls. The measurements were carried out at 7, 14, and 21 days in vitro (DIV) to assess the effect of time in culture on Ca²⁺ dynamics. We observed that both time and differentiation treatment are important factors associated with a reduced fraction of cells showing Ca²⁺ oscillations, paralleled by increased IPI times, in comparison with untreated ASCs. Both adipogenic and osteogenic differentiation resulted in a reduction in Ca²⁺ dynamics, such as the fraction of cells showing intracellular Ca²⁺ oscillations and their frequency. Adipogenic differentiation was associated with a more pronounced reduction of Ca²⁺ dynamics compared to cells differentiating towards the osteogenic fate. Changes in Ca²⁺ associated oscillations with a specific treatment had already occurred at 7 DIV. Finally, we observed a reduction in Ca²⁺ dynamics over time in untreated ASCs. These data suggest that adipogenic and osteogenic differentiation cell fates are associated with specific changes in spontaneous Ca²⁺ dynamics over time. While this observation is interesting and provides useful information to understand the functional correlates of stem cell differentiation, further studies are required to clarify the molecular and mechanistic correlates of these changes. This will allow us to better understand the causal relationship between Ca²⁺ dynamics and differentiation, potentially leading to the development of novel, more effective interventions for both bone regeneration and control of adipose growth.

• adipogenic differentiation
• adipose-derived stem cells
• calcium oscillations
• mesenchymal stem cells
• osteogenic differentiation

• Adipocytes/cytology
• Adipogenesis/genetics
• Calcium/metabolism
• Calcium Signaling/genetics
• Cell Differentiation/genetics
• Cell Line
• Cell Lineage/genetics
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteocytes/cytology
• Osteogenesis/genetics
• Regenerative Medicine

• bone
• cilium-related bone disease
• hard tissue
• mechanical sensing
• primary cilia
• tooth

• Electrical stimulation
• bone regeneration
• computational modelling
• faradic by-products
• mesenchymal stem/stromal cells

Calcium (Ca²⁺) signalling plays an indispensable role in dental pulp and dentin regeneration, but the Ca²⁺ responses of human dental pulp stem cells (hDPSCs) stimulated with tricalcium silicate-based (TCS-based) dental biomaterials remains largely unexplored. The objective of the present study was to identify and correlate extracellular Ca²⁺ concentration, intracellular Ca²⁺ dynamics, pH, cytotoxicity, gene expression and mineralization ability of human dental pulp stem cells (hDPSCs) stimulated with two different TCS-based biomaterials: Biodentine and ProRoot white MTA. The hDPSCs were exposed to the biomaterials, brought in contact with the overlaying medium, with subsequent measurements of extracellular Ca²⁺ and pH, and intracellular Ca²⁺ changes. Messenger RNA expression (BGLAP, TGF-β, MMP1 and BMP2), cytotoxicity (MTT and TUNEL) and mineralization potential (Alizarin red and Von Kossa staining) were then evaluated. Biodentine released significantly more Ca²⁺ in the α-MEM medium than ProRoot WMTA but this had no cytotoxic impact on hDPSCs. The larger Biodentine-linked Ca²⁺ release resulted in altered intracellular Ca²⁺ dynamics, which attained a higher maximum amplitude, faster rise time and increased area under the curve of the Ca²⁺ changes compared to ProRoot WMTA. Experiments with intracellular Ca²⁺ chelation, demonstrated that the biomaterial-triggered Ca²⁺ dynamics affected stem cell-related gene expression, cellular differentiation and mineralization potential. In conclusion, biomaterial-specific Ca²⁺ dynamics in hDPSCs determine differentiation and mineralization outcomes, with increased Ca²⁺ dynamics enhancing mineralization.

• Biophysical tools
• Calcium homoeostasis
• Cell morphology
• Cellular biomechanics
• Mesenchymal stem cells
• Osteogenic differentiation

Electric fields are involved in numerous physiological processes, including directional embryonic development and wound healing following injury. To study these processes in vitro and/or to harness electric field stimulation as a biophysical environmental cue for organised tissue engineering strategies various electric field stimulation systems have been developed. These systems are overall similar in design and have been shown to influence morphology, orientation, migration and phenotype of several different cell types. This review discusses different electric field stimulation setups and their effect on cell response.

• Biophysical cues
• Cell stimulation
• Electric field
• Galvanotaxis

Due to the ageing population, there is a steadily increasing incidence of osteoporosis and osteoporotic fractures. As conventional pharmacological therapy options for osteoporosis are often associated with severe side effects, bone grafts are still considered the clinical gold standard. However, the availability of viable, autologous bone grafts is limited making alternative cell-based strategies a promising therapeutic alternative. Adipose-derived stem cells (ASCs) are a readily available population of mesenchymal stem/stromal cells (MSCs) that can be isolated within minimally invasive surgery. This ease of availability and their ability to undergo osteogenic differentiation makes ASCs promising candidates for cell-based therapies for bone fractures. Recent studies have suggested that both exposure to electrical fields and cultivation in 3D can positively affect osteogenic potential of MSCs. To elucidate the osteoinductive potential of a combination of these biophysical cues on ASCs, cells were embedded within anionic nanofibrillar cellulose (aNFC) hydrogels and exposed to electrical stimulation (ES) for up to 21 days. ES was applied to ASCs in 2D and 3D at a voltage of 0.1 V/cm with a duration of 0.04 ms, and a frequency of 10 Hz for 30 min per day. Exposure of ASCs to ES in 3D resulted in high alkaline phosphatase (ALP) activity and in an increased mineralisation evidenced by Alizarin Red S staining. Moreover, ES in 3D aNFC led to an increased expression of the osteogenic markers osteopontin and osteocalcin and a rearrangement and alignment of the actin cytoskeleton. Taken together, our data suggest that a combination of ES with 3D cell culture can increase the osteogenic potential of ASCs. Thus, exposure of ASCs to these biophysical cues might improve the clinical outcomes of regenerative therapies in treatment of osteoporotic fractures.

• 3D cell culture
• adipose-derived stem cells
• electrical stimulation
• nanofibrillar cellulose
• osteogenic differentiation

The ability of a single Ca²⁺ ion to play an important role in cell biology is highlighted by the need for cells to form Ca²⁺ signals in the dimensions of space, time, and amplitude. Thus, spatial and temporal changes in intracellular Ca²⁺ concentration are important for determining cell fate. Optogenetic technology has been developed to provide more precise and targeted stimulation of cells. Here, U2OS cells overexpressing Ca²⁺ translocating channelrhodopsin (CatCh) were used to mediate Ca²⁺ influx through blue light illumination with various parameters, such as intensity, frequency, duty cycle, and duration. We identified that several Ca²⁺‐dependent transcription factors and certain kinases can be activated by specific Ca²⁺ waves. Using a wound‐healing assay, we found that low‐frequency Ca²⁺ oscillations increased cell migration through the activation of NF‐κB. This study explores the regulation of cell migration by Ca²⁺ signals. Thus, we can choose optical parameters to modulate Ca²⁺ waves and achieve activation of specific signaling pathways. This novel methodology can be applied to clarify related cell‐signaling mechanisms in the future.

• Ca2+ translocating channelrhodopsin
• Ca2+-dependent transcription factors
• cell migration
• channelrhodopsin-2
• optogenetics

Human cardiac stem cells expressing the W8B2 marker (W8B2⁺ CSCs) were recently identified and proposed as a new model of multipotent CSCs capable of differentiating into smooth muscle cells, endothelial cells and immature myocytes. Nevertheless, no characterization of ion channel or calcium activity during the differentiation of these stem cells has been reported.

The objectives of this study were thus to analyze (using the TaqMan Low-Density Array technique) the gene profile of W8B2⁺ CSCs pertaining to the regulation of ion channels, transporters and other players involved in the calcium homeostasis of these cells. We also analyzed spontaneous calcium activity (via the GCaMP calcium probe) during the in vitro differentiation of W8B2⁺ CSCs into cardiac myocytes.

Our results show an entirely different electrophysiological genomic profile between W8B2⁺ CSCs before and after differentiation. Some specific nodal genes, such as Tbx3, HCN, ICaT, L, KV, and NCX, are overexpressed after this differentiation. In addition, we reveal spontaneous calcium activity or a calcium clock whose kinetics change during the differentiation process. A pharmacological study carried out on differentiated W8B2⁺ CSCs showed that the NCX exchanger and IP3 stores play a fundamental role in the generation of these calcium oscillations.

Taken together, the present results provide important information on ion channel expression and intrinsic calcium dynamics during the differentiation process of stem cells expressing the W8B2 marker.

• Calcium activity
• Cardiac differentiation
• GCaMP
• Ion channels
• Oscillations
• W8B2+ human cardiac stem cell

• Ca(2+) signaling
• Mitochondrial-nuclear interactions
• Regenerative potential
• Stem cell plasticity

In the last years, microdosimetric numerical models of cells including intracellular compartments have been proposed, aiming to investigate the poration induced by the application of nanosecond pulsed electric fields (nsPEFs). A limitation of such models was the extremely approximate cell and organelle shapes, leading to an incorrect estimation of the electric field or transmembrane potential distribution in the studied domain. In order to obtain a reliable model of in vitro experiments and a one-to-one comparison between experimental and simulated results, here, a realistic model of 12 human mesenchymal stem cells was built starting from their optical microscopy images where different cell compartments were highlighted. The microdosimetric analysis of the cells group was quantified in terms of electric field and transmembrane potentials (TMPs) induced by an externally applied 10-ns trapezoidal pulse with rise and fall times of 2 ns, with amplitudes ranging from 2 to 30 MV/m. The obtained results showed that the plasma and endoplasmic reticulum (ER) membrane of each cell respond in a different way to the same electric field amplitude, depending on differences in shape, size, and position of the single cell with respect to the applied electric field direction. Therefore, also the threshold for an efficient electroporation is highly different from cell to cell. This difference was quantitatively estimated through the cumulative distribution function of the pore density for the plasma and ER membrane of each cell, representing the probability that a certain percentage of membrane has reached a specific value of pore density. By comparing the dose-response curves resulted from the simulations and those from the experimental study of De Menorval et al. (2016), we found a very good matching of results for plasma and ER membrane when 2% of the porated area is considered sufficient for permeabilizing the membrane. This result is worth of noting as it highlights the possibility to effectively predict the behavior of a cell (or of a population of cells) exposed to nsPEFs. Therefore, the microdosimetric realistic model described here could represent a valid tool in setting up more efficient and controlled electroporation protocols.

• confocal fluorescence microscopy
• electropermeabilization
• electroporation
• endoplasmic reticulum
• microdosimetry
• nanoporation experiments
• nanosecond pulses
• realistically shaped cell models

• Conjunctiva mesenchymal stem cells
• Nanofibrous scaffold
• Photoreceptor differentiation
• miR-9 overexpression

• Bone regeneration
• Bone tissue engineering
• Electrical stimulation
• In vitro
• In vivo

• Adenosine Triphosphate/metabolism
• Apoptosis
• Bone Regeneration
• Bone and Bones
• Calcium Signaling
• Cell Adhesion
• Cell Differentiation
• Cell Movement
• Cell Proliferation
• Chondrogenesis
• Dental Pulp/cytology
• Electric Stimulation/methods
• Electric Stimulation Therapy/methods
• Fracture Healing
• Guided Tissue Regeneration/methods
• Heat-Shock Proteins/metabolism
• Humans
• In Vitro Techniques
• Inflammation
• MAP Kinase Signaling System
• Mechanotransduction, Cellular
• Membrane Microdomains
• Mesenchymal Stem Cells
• Neovascularization, Physiologic
• Osteoblasts
• Osteogenesis
• Reactive Oxygen Species/metabolism
• Receptors, Cell Surface/metabolism
• Signal Transduction
• Tissue Engineering/methods
• Tissue Scaffolds

The recent discovery of bone flexoelectricity (strain-gradient-induced electrical polarization) suggests that flexoelectricity could have physiological effects in bones, and specifically near bone fractures, where flexoelectricity is theoretically highest. Here, we report a cytological study of the interaction between crack stress and bone cells. We have cultured MC3T3-E1 mouse osteoblastic cells in biomimetic microcracked hydroxyapatite substrates, differentiated into osteocytes and applied a strain gradient to the samples. The results show a strong apoptotic cellular response, whereby mechanical stimulation causes those cells near the crack to die, as indicated by live-dead and caspase staining. In addition, analysis two weeks post-stimulation shows increased cell attachment and mineralization around microcracks and a higher expression of osteocalcin –an osteogenic protein known to be promoted by physical exercise. The results are consistent with flexoelectricity playing at least two different roles in bone remodelling: apoptotic trigger of the repair protocol, and electro-stimulant of the bone-building activity of osteoblasts.

Stem cells can be conceptualized as computational processors capable of sensing, processing, and converting environmental information (input) to yield a specific differentiation pathway (output). In this study, we employ a temperature-controlled polymer sheet actuator to interpret and transfer information, controlled by the material’s programming, to mesenchymal stem cells. The cell’s interpretation of mechanical, thermal, and biochemical signaling is shown to be dependent on the actuator’s activity, utilized to accelerate differentiation toward bone cells, further elucidating the role of microenvironmental parameters on mammalian cells. Our method provides a unique approach to processing two discrete stimuli into one biochemical signal, calcium ions, providing a basis for the logical control of the flow of biological signals and the design of cellular functions.

Stem cells are capable of sensing and processing environmental inputs, converting this information to output a specific cell lineage through signaling cascades. Despite the combinatorial nature of mechanical, thermal, and biochemical signals, these stimuli have typically been decoupled and applied independently, requiring continuous regulation by controlling units. We employ a programmable polymer actuator sheet to autonomously synchronize thermal and mechanical signals applied to mesenchymal stem cells (MSCs). Using a grid on its underside, the shape change of polymer sheet, as well as cell morphology, calcium (Ca²⁺) influx, and focal adhesion assembly, could be visualized and quantified. This paper gives compelling evidence that the temperature sensing and mechanosensing of MSCs are interconnected via intracellular Ca²⁺. Up-regulated Ca²⁺ levels lead to a remarkable alteration of histone H3K9 acetylation and activation of osteogenic related genes. The interplay of physical, thermal, and biochemical signaling was utilized to accelerate the cell differentiation toward osteogenic lineage. The approach of programmable bioinstructivity provides a fundamental principle for functional biomaterials exhibiting multifaceted stimuli on differentiation programs. Technological impact is expected in the tissue engineering of periosteum for treating bone defects.

• HDAC1
• RUNX2
• calcium influx
• mesenchymal stem cells
• reversible shape-memory actuator

• inflammation
• macrophages (THP-1s)
• mesenchymal stem cells (MSCs)
• muscle cells (C2C12)
• pulsed electromagnetic field (PEMF)
• regeneration

• Wnt/Ca2+ signaling pathway
• bismuth sulfide/hydroxyapatite
• bone regeneration
• implants
• photoelectrons

• Bismuth/chemistry
• Bone Regeneration
• Cell Differentiation
• Durapatite/chemistry
• Electrons
• Extracellular Matrix/metabolism
• Humans
• Infrared Rays
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Photochemical Processes
• Sulfides/chemistry
• Tissue Engineering

The anti-inflammatory and immunomodulatory properties of human mesenchymal stromal cells (MSCs) are a focus within regenerative medicine. However, 2D cultivation of MSCs for extended periods results in abnormal cell polarity, chromosomal changes, reduction in viability, and altered differentiation potential. As an alternative, various 3D hydrogels have been developed which mimic the endogenous niche of MSCs. Nevertheless, imaging cells embedded within 3D hydrogels often suffers from low signal-to-noise ratios which can be at least partly attributed to the high light absorbance and light scattering of the hydrogels in the visible light spectrum. In this study, human adipose tissue-derived MSCs (ADSCs) are cultivated within an anionic nanofibrillar cellulose (aNFC) hydrogel. It is demonstrated that aNFC forms nanofibres arranged as a porous network with low light absorbance in the visible spectrum. Moreover, it is shown that aNFC is cytocompatible, allowing for MSC proliferation, maintaining cell viability and multilineage differentiation potential. Finally, aNFC is compatible with scanning electron microscopy (SEM) and light microscopy including the application of conventional dyes, fluorescent probes, indirect immunocytochemistry, and calcium imaging. Overall, the results indicate that aNFC represents a promising 3D material for the expansion of MSCs whilst allowing detailed examination of cell morphology and cellular behaviour.

• bone regeneration
• electrical stimulation
• faradic by-products
• macrophages
• preosteoblasts

• Cell transplantation
• Clinical practice
• Epigenetics
• In vitro differentiation
• Physical stimuli
• Self-renewal
• Stem cell fate
• Stem cells

• Cytosolic Ca2+ regulation
• Decidualization
• Endometrial stromal cells
• Ion channels
• Proliferation

• Adult
• Antigens, CD/metabolism
• Calcium/metabolism
• Calcium Release Activated Calcium Channels/metabolism
• Calcium Signaling
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Decidua/cytology
• Decidua/metabolism
• Endometrium/cytology
• Endometrium/metabolism
• Endoplasmic Reticulum/metabolism
• Female
• Humans
• Inositol 1,4,5-Trisphosphate Receptors/metabolism
• Stromal Cells/metabolism
• Stromal Interaction Molecules/metabolism

• degeneration
• hydrogel
• intervertebral disc
• regeneration

• MR/P026796/1 Medical Research Council

• CALCIUM CHANNEL/OSCILLATION
• GαI SIGNALING
• OSTEOBLASTS
• RGS12

• Animals
• Calcium Channels, L-Type/genetics
• Calcium Channels, L-Type/metabolism
• Calcium Signaling
• Cell Differentiation
• Female
• GTP-Binding Protein alpha Subunits/genetics
• GTP-Binding Protein alpha Subunits/metabolism
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Knockout
• Osteoblasts/metabolism
• Osteogenesis/genetics
• RGS Proteins/genetics
• RGS Proteins/metabolism

• P30 AR069619 NIAMS NIH HHS
• R01 AR066101 NIAMS NIH HHS
• R01 DE023105 NIDCR NIH HHS
• R01 AG048388 NIA NIH HHS
• AR066101 National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS]
• AG048388 NIH (National Institute on Aging [NIA]
• DE023105 National Institute of Dental and Craniofacial Research [NIDCR]

Hypoxia-inducible factor 1 (HIF1) is a master transcription factor that induces the transcription of genes involved in the metabolism and behavior of stem cells. HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of stem cells under hypoxic conditions. HIF1 activity is well known to be tightly controlled by the alpha subunit of HIF1 (HIF1α). Understanding the regulatory mechanisms that control HIF1 activity in stem cells will provide novel insights into stem cell biology under hypoxia. Recent research has unraveled the mechanistic details of HIF1α regulating processes, suggesting new strategies for regulating stem cells. This review summarizes recent experimental studies on the role of several regulatory factors (including calcium, 2-oxoglutarate-dependent dioxygenase, microtubule network, importin, and coactivators) in regulating HIF1α activity in stem cells.

• 2-Oxoglutrate-dependent dioxygenase (2OGDD)
• Calcium
• Hypoxia-inducible factor 1 alpha (HIF1α)
• Importin
• Microtubule
• Stem cells

• calcium
• fibrocartilage
• mechanobiology
• mechanotransduction
• tendon

• Calcium/metabolism
• Calcium/physiology
• Calcium Signaling/physiology
• Cells, Cultured
• Electric Stimulation
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/physiology
• Osteogenesis/physiology

• Bone and cartilage regeneration
• electrical and magnetic fields
• fracture repair
• mechanical forces
• physical stimulation
• shock waves
• ultrasound

• R21 AR075196 NIAMS NIH HHS
• R21 EB024787 NIBIB NIH HHS

• Differentiation
• Intracellular Ca(2+) signaling
• Optogenetics
• Osteoblast