• adipose-derived mesenchymal stem cells
• immune system
• inflammation
• licensing
• regenerative medicine

• Homing
• Inflammatory microenvironment
• Mesenchymal stem cell
• Spinal cord injury

• Humans
• Mesenchymal Stem Cell Transplantation
• Spinal Cord Injuries/therapy
• Neurons
• Chemokines
• Mesenchymal Stem Cells
• Spinal Cord

• TNF-α
• exosomal microvesicles
• immunomodulation
• mesenchymal stem cells
• tissue regeneration and repair

• BMSCs
• Biomaterial
• Inflammation
• Macrophages
• Tissue regeneration

• Differentiation
• Exosome
• Mesenchymal stromal cells (MSCs)
• Paracrine factors
• Wound healing

• Exosomes/metabolism
• Humans
• Mesenchymal Stem Cells/metabolism
• MicroRNAs/metabolism
• Quality of Life
• Skin/metabolism
• Wound Healing

• Cutaneous wounds
• Differentiation
• Exosome
• Mesenchymal stem/stromal stem cell (MSC)
• Paracrine factors

• Exosomes/metabolism
• Fibroblasts
• Mesenchymal Stem Cells/metabolism
• Skin
• Wound Healing/physiology

• Bone biology
• Bone regeneration
• Bone tissue engineering
• Cytokine
• Scaffold

Mesenchymal stem/stromal cells (MSCs) have an immunoregulatory capacity and have been used in different clinical protocols requiring control of the immune response. However, variable results have been obtained, mainly due to the effect of the microenvironment on the induction, increase, and maintenance of MSC immunoregulatory mechanisms. In addition, the importance of cell–cell contact for MSCs to efficiently modulate the immune response has recently been highlighted. Because these interactions would be difficult to achieve in the physiological context, the release of extracellular vesicles (EVs) and their participation as intermediaries of communication between MSCs and immune cells becomes relevant. Therefore, this article focuses on analyzing immunoregulatory mechanisms mediated by cell contact, highlighting the importance of intercellular adhesion molecule-1 (ICAM-1) and the participation of EVs. Moreover, the effects of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), the main cytokines involved in MSC activation, are examined. These cytokines, when used at the appropriate concentrations and times, would promote increases in the expression of immunoregulatory molecules in the cell and allow the acquisition of EVs enriched with these molecules. The establishment of certain in vitro activation guidelines will facilitate the design of conditioning protocols to obtain functional MSCs or EVs in different pathophysiological conditions.

• cell–cell contact
• extracellular vesicles
• immunoregulation
• mesenchymal stem/stromal cells

Human umbilical cord Wharton’s jelly derived mesenchymal stem cells (hUCMSCs), a source of cell therapy, have received a great deal of attention due to their homing or migrating ability in response to signals emanating from damaged sites. It has been found that IL-1β possesses the ability to induce the expression of matrix metalloproteinase-3 (MMP-3) in bone marrow MSCs. MMP-3 is involved in cell migration in various types of cells, including glioblastoma, vascular smooth muscle, and adult neural progenitor cells. In this study, we proposed that IL-1β influences hUCMSCs migration involving MMP-3. The expression level of MMP-3 in IL-1β-induced hUCMSCs was verified using cDNA microarray analysis, quantitative real-time PCR, ELISA and Western blot. Wound-healing and trans-well assay were used to investigate the cell migration and invasion ability of IL-1β-treated hUCMSCs. In addition, we pre-treated hUCMSCs with interleukin-1 receptor antagonist, MMP-3 inhibitors (ALX-260-165, UK 356618), or transfected with MMP-3 siRNA to confirm the role of MMP3 in IL-1β-induced cell migration. Our results showed that IL-1β induced MMP-3 expression is related to the migration of hUCMSCs. Moreover, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126, p38 inhibitor SB205380, JNK inhibitor SP600125 and Akt inhibitor GSK 690693 decreased IL-1β-induced MMP-3 mRNA and protein expression. The migration and invasion ability analyses showed that these inhibitors attenuated the IL-1β-induced migration and invasion ability of hUCMSCs. In conclusion, we have found that IL-1β induces the expression of MMP-3 through ERK1/2, JNK, p38 MAPK and Akt signaling pathways to enhance the migration of hUCMSCs. These results provide further understanding of the mechanisms in IL-1β-induced hUCMSCs migration to injury sites.

Renal failure has a high prevalence and is becoming a public health problem worldwide. However, the renal replacement therapies such as dialysis are not yet satisfactory for its multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidney and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidney in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis, and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.

• Kidney
• Microenvironment
• Stem/progenitor cells
• Therapy

Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory capacity; therefore, they have been used in different clinical protocols in which it is necessary to decrease the immune response. This capacity is mainly regulated by TNF-α and IFN-γ, and it has been observed that cell-cell contact, mainly mediated by ICAM-1, is important for MSCs to carry out efficient immunoregulation. Therefore, in the present work, we analyzed the effect of TNF-α alone or in combination with IFN-γ on the expression of ICAM-1. Besides, given the importance of cell contact in the immunoregulatory function of MSCs, we analyzed whether these cells release ICAM-1⁺ microvesicles (MVs). Our results show for the first time that TNF-α is capable of increasing the early expression of ICAM-1 in human BM-MSCs. Also, we observed that TNF-α and IFN-γ have a synergistic effect on the increase in the expression of ICAM-1. Furthermore, we found that BM-MSCs exposed to an inflammatory environment release MVs enriched in ICAM-1 (MVs-ICAM-1^high). The knowledge generated in this study will contribute to the improvement of in vitro conditioning protocols that favor the therapeutic effect of these cells or their products.

Curcumin, a hydrophobic polyphenol derived from turmeric, has been used a food additive and as a herbal medicine for the treatment of various diseases, but the clinical application of curcumin is restricted by its poor aqueous solubility and its low permeability and bioavailability levels. In the present study, we investigate the functional role of a nanosphere loaded with curcumin (CN) in the promotion of the motility of human mesenchymal stem cells (MSCs) during the skin wound healing process. CN significantly increased the motility of umbilical cord blood (UCB)-MSCs and showed 10,000-fold greater migration efficacy than curcumin. CN stimulated the phosphorylation of c-Src and protein kinase C which are responsible for the distinctive activation of the MAPKs. Interestingly, CN significantly induced the expression levels of α-actinin-1, profilin-1 and filamentous-actin, as regulated by the phosphorylation of nuclear factor-kappa B during its promotion of cell migration. In a mouse skin excisional wound model, we found that transplantation of UCB-MSCs pre-treated with CN enhanced wound closure, granulation, and re-epithelialization at mouse skin wound sites. These results indicate that CN is a functional agent that promotes the mobilization of UCB-MSCs for cutaneous wound repair.

• UCB-MSCs
• c-Src
• curcumin nanospheres
• motility
• wound repair

• Cell differentiation
• Graphene Oxide
• Implants
• Macrophages
• Osteoblasts
• Titanium

To determine whether priming of bone marrow mesenchymal stem cells (MSCs) by signals from injured retina, particularly tumor necrosis factor α (TNFα), increase their exosomes’ neuroprotective efficacy on retinal ganglion cells (RGCs).

MSCs were primed with retinal cell culture conditioned medium, with or without the TNFα blocker etanercept or TNFα prior to isolation of exosomes. MSC conditioned medium or exosomes were added to rat retinal cultures or human stem cell–derived retinal ganglion cell (hRGC) cultures, and RGC neuroprotective effects were quantified. Luminex assays were used to compare primed versus unprimed exosomes.

MSC conditioned medium and exosomes exerted a significant neuroprotective effect on injured rat and hRGC. This effect was significantly increased after MSCs were primed with retinal conditioned medium or TNFα. Blocking of TNFα signaling with etanercept prevented priming-induced RGC neuroprotective efficacy. Priming increased Pigment epithelium-derived factor (PEDF) and VEGF-AA exosomal abundance.

MSC exosomes promote RGC survival not just in rodent retinal cultures but also with hRGC. Their efficacy can be further enhanced through TNFα priming with the mechanism of action potentially mediated, at least in part, through increased levels of PEDF and VEGF-AA.

• Acellular foreskin
• Human umbilical cord mesenchymal stem cells
• Lactobacillus acidophilus
• Migration
• Monophosphoryl lipid A

• Biocompatible Materials
• Bone Regeneration
• Guided Tissue Regeneration
• Membranes, Artificial

Vascular calcification (VC), characterized by hydroxyapatite crystal depositing in the vessel wall, is a common pathological condition shared by many chronic diseases and an independent risk factor for cardiovascular events. Recently, VC is regarded as an active, dynamic cell-mediated process, during which calcifying cell transition is critical. Mesenchymal stem cells (MSCs), with a multidirectional differentiation ability and great potential for clinical application, play a duplex role in the VC process. MSCs facilitate VC mainly through osteogenic transformation and apoptosis. Meanwhile, several studies have reported the protective role of MSCs. Anti-inflammation, blockade of the BMP2 signal, downregulation of the Wnt signal, and antiapoptosis through paracrine signaling are possible mechanisms. This review displays the evidence both on the facilitating role and on the protective role of MSCs, then discusses the key factors determining this divergence.

• Biomaterial enhanced regeneration
• degradable/regenerative scaffolds
• fracture fixation
• skin regeneration

• R49/CCR403641 Centers for Disease Control and Prevention

• Carcinogenesis
• Chemotaxis
• Hepatocellular carcinoma (HCC)
• Mesenchymal stromal cells (MSCs)
• Neoplasm metastasis
• Tumor-targeted therapy

• Animals
• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/pathology
• Cell Movement/physiology
• Disease Progression
• Humans
• Liver Neoplasms/pathology
• Mesenchymal Stem Cells/pathology
• Tumor Microenvironment/physiology

• National Natural Science Foundation of China

Pressure ulcers are one of the most common forms of skin injury, particularly in the spinal cord injured (SCI). Pressure ulcers are difficult to heal in this population requiring at least six months of bed rest. Surgical treatment (grafting) is the fastest recovery time, but it still requires six weeks of bed rest plus significant additional costs and a high recurrence rate. A significant clinical benefit would be obtained by speeding the healing rate of a non-surgical treatment to close to that of surgical treatment (approximately doubling of healing rate). Current non-surgical treatment is mostly inactive wound coverings. The goal of this project was to look at the feasibility of doubling the healing rate of a full-thickness defect using combinations of three treatments, for the first time, each shown to increase healing rate: application of transforming growth factor-β₃ (TGF-β₃), an albumin based scaffold, and mesenchymal stem cells (MSCs). At one week following surgery, the combined treatment showed the greatest increase in healing rate, particularly for the epithelialization rate. Although the target level of a 100% increase in healing rate over the control was not quite achieved, it is anticipated that the goal would be met with further optimization of the treatment.

• TGF-β3
• albumin scaffold
• mesenchymal stem cells
• pressure ulcers
• wound healing

Local anesthetics (LAs) are commonly used to provide peri-operative pain control in the peripheral joints. In the field of regenerative medicine, adipose-derived mesenchymal stem cells (ADMSCs) are gaining attention as a cellular source for repair and regeneration in degenerative diseases. However, previous studies have demonstrated that the commonly used drugs lidocaine, ropivacaine, bupivacaine and mepivacaine may be toxic to human chondrocytes, which has raised concerns over whether they exert similar negative effects on ADMSCs during early chondrogenic differentiation. In the present in vitro study, the cytotoxicity of different LAs to ADMSCs was determined during early chondrogenic differentiation. At concentrations similar to those after physiological dilution once injected into the degenerative tissues, LAs (1% lidocaine, 0.5% bupivacaine, 0.5% ropivacaine or 2% mepivacaine) and PBS (control group) were incubated with rabbit ADMSCs (rADMSCs) for 60 min. Following further culture for 3 or 7 days, the cell viability, apoptosis and morphological alterations of chondrogenic differentiation were measured by determining the mitochondrial activity, by flow cytometric analysis, Safranine Fast Green double staining and reverse transcription-quantitative polymerase chain reaction of chondrogenesis-associated genes. The results indicated that the mitochondrial activity in rADMSC was decreased and the apoptotic rate was increased, following treatment with LAs (P<0.05). Lidocaine (1%) was less cytotoxic to rADMSCs during early chondrogenesis compared with other LAs. The expression levels of chondrogenesis-associated markers, including collagen I, collagen III and sex-determining region Y box 9 were all decreased at day 3 following exposure to LAs compared with the control group (P<0.05). The expression levels of these chondrogenesis-associated genes began to increase on day 7 following exposure but remained lower compared with the control group (P<0.05). Of note, 2% mepivacaine and 1% lidocaine exhibited a less pronounced negative effect on chondrogenesis-associated gene expression compared with other LAs. Therefore, the present study concluded that LAs are cytotoxic to rADMSCs during early chondrogenesis. Attention should be paid to the different types of LA selected in conjunction with ADMSC injection therapy.

• chondrogenic differentiation
• cytotoxicity
• local anesthetics
• mesenchymal stem cells

• Chemotaxis
• Mesenchymal stem cells
• Microfluidics
• Stiffness

Mesenchymal stem cells (MSCs) are known for homing to sites of injury in response to signals of cellular damage. However, the mechanisms of how cytokines recruit stem cells to target tissue are still unclear. In this study, we found that the proinflammation cytokine interleukin-1β (IL-1β) promotes mesenchymal stem cell migration. The cDNA microarray data show that IL-1β induces matrix metalloproteinase-1 (MMP-1) expression. We then used quantitative real-time PCR and MMP-1 ELISA to verify the results. MMP-1 siRNA transfected MSCs, and MSC pretreatment with IL-1β inhibitor interleukin-1 receptor antagonist (IL-1RA), MMP tissue inhibitor of metalloproteinase 1 (TIMP1), tissue inhibitor of metalloproteinase 2 (TIMP2), MMP-1 inhibitor GM6001, and protease-activated receptor 1 (PAR1) inhibitor SCH79797 confirms that PAR1 protein signaling pathway leads to IL-1β-induced cell migration. In conclusion, IL-1β promotes the secretion of MMP-1, which then activates the PAR1 and G-protein-coupled signal pathways to promote mesenchymal stem cell migration.

• brain-derived neurotrophic
• erythropoietin
• factor
• hypoxia inducible
• matrix metalloproteinase
• neonatal
• stromal cell-derived
• vascular endothelial growth

• CAR-T
• Mesenchymal stem cells
• Stem cell

• Biocompatible Materials
• Bone Regeneration/immunology
• Humans
• Immune System Phenomena
• Nanotechnology
• Osteogenesis/immunology
• Surface Properties

• adhesion
• adipose tissue–derived stem cells
• homing
• rolling

Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury and are possibly attracted by inflammatory factors. As a proinflammatory mediator, angiotensin II (Ang II) reportedly enhances the migration of various cell types by signaling via the Ang II receptor in vitro. However, few studies have focused on the effects of Ang II on MSC migration and the underlying mechanisms.

Human bone marrow MSCs migration was measured using wound healing and Boyden chamber migration assays after treatments with different concentrations of Ang II, an AT1R antagonist (Losartan), and/or an AT2R antagonist (PD-123319). To exclude the effect of proliferation on MSC migration, we measured MSC proliferation after stimulation with the same concentration of Ang II. Additionally, we employed the focal adhesion kinase (FAK) inhibitor PF-573228, RhoA inhibitor C3 transferase, Rac1 inhibitor NSC23766, or Cdc42 inhibitor ML141 to investigate the role of cell adhesion proteins and the Rho-GTPase protein family (RhoA, Rac1, and Cdc42) in Ang II-mediated MSC migration. Cell adhesion proteins (FAK, Talin, and Vinculin) were detected by western blot analysis. The Rho-GTPase family protein activities were assessed by G-LISA and F-actin levels, which reflect actin cytoskeletal organization, were detected by using immunofluorescence.

Human bone marrow MSCs constitutively expressed AT1R and AT2R. Additionally, Ang II increased MSC migration in an AT2R-dependent manner. Notably, Ang II-enhanced migration was not mediated by Ang II-mediated cell proliferation. Interestingly, Ang II-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased Talin and Vinculin expression. Moreover, RhoA and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction. Furthermore, FAK, Talin, and Vinculin activation and F-actin reorganization in response to Ang II were prevented by PD-123319 but not Losartan, indicating that FAK activation and F-actin reorganization were downstream of AT2R.

These data indicate that Ang II-AT2R regulates human bone marrow MSC migration by signaling through the FAK and RhoA/Cdc42 pathways. This study provides insights into the mechanisms by which MSCs home to injury sites and will enable the rational design of targeted therapies to improve MSC engraftment.

• AT1R
• AT2R
• Angiotensin II
• Cell migration
• F-actin
• Focal adhesion kinase
• Mesenchymal stem cells
• Rho GTPases

A critical step of MSCs therapy is dependent on its ability to migrate into the sites of injury, so various approaches have been introduced to boost the migratory ability of MSCs. PGE2 is the major prostaglandin generated by COX enzymes and has been implicated in inflammatory response. Evidence indicates that PGE2 can facilitate MSCs migration. Further exploration of the underlying molecular mechanism participating in the promigratory ability of PGE2 may provide a novel strategy to improve MSC transplantation efficacy. In this study, our findings suggested that EP2 prostanoid receptor promotes MSCs migration through activation of FAK and ERK1/2 pathways. Furthermore, MSCs migration induced by PGE2 was blunted by FAK or ERK1/2 inhibitors. EP2-mediated MSCs migration depends on the activation of FAK and ERK1/2. However, the current study did not investigate the migration of MSCs over a blood vessel endothelial barrier. In conclusion, our findings reveal EP2-mediated FAK and ERK1/2 activation was essential for MSCs migration induced by PGE2, indicating that activation of EP2 receptor and FAK/ERK pathways may be a promising strategy to accelerate homing efficiency of MSCs, which in turn enhances therapeutic potential of MSCs transplantation.

• N-cadherin
• mesenchymal stem cells
• migration
• transforming growth factor β

• Animals
• Antigens, CD/genetics
• Antigens, CD/metabolism
• Bone Marrow Cells/drug effects
• Bone Marrow Cells/metabolism
• Cadherins/antagonists & inhibitors
• Cadherins/genetics
• Cadherins/metabolism
• Cell Movement/drug effects
• Cells, Cultured
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Focal Adhesion Kinase 1/metabolism
• Humans
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Mice
• Neuropeptides/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• RNA Interference
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta/agonists
• Receptors, Transforming Growth Factor beta/metabolism
• Signal Transduction/drug effects
• Transfection
• Transforming Growth Factor beta1/pharmacology
• p38 Mitogen-Activated Protein Kinases/metabolism
• rac1 GTP-Binding Protein/metabolism
• src-Family Kinases/metabolism

Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further.

• DAMP
• healing
• inflammation
• stem cells
• trauma

• Animals
• Cell Differentiation
• Humans
• Inflammation/etiology
• Multiple Organ Failure/etiology
• Muscles/pathology
• Muscles/physiology
• Neovascularization, Physiologic
• Regeneration
• Stem Cell Research
• Stem Cells/cytology
• Stem Cells/physiology
• Wound Healing/physiology
• Wounds and Injuries/etiology
• Wounds and Injuries/pathology
• Wounds and Injuries/therapy

The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor-α (TNF-α) increased the level of vascular cell adhesion molecule-1 (VCAM-1) expression in a dose-dependent manner. The nuclear factor-κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM-1 expression induced by TNF-α at the mRNA and protein levels (P<0.05). TNF-α augmented the activation of NF-κB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF-κB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NF-κB, ERK and JNK signaling pathways.

The skeleton is a highly dynamic tissue whose structure relies on the balance between bone deposition and resorption. This equilibrium, which depends on osteoblast and osteoclast functions, is controlled by multiple factors that can be modulated post-translationally. Some of the modulators are Mitogen-activated kinases (MAPKs), whose role has been studied in vivo and in vitro. p38-MAPK modifies the transactivation ability of some key transcription factors in chondrocytes, osteoblasts and osteoclasts, which affects their differentiation and function. Several commercially available inhibitors have helped to determine p38 action on these processes. Although it is frequently mentioned in the literature, this chemical approach is not always as accurate as it should be. Conditional knockouts are a useful genetic tool that could unravel the role of p38 in shaping the skeleton. In this review, we will summarize the state of the art on p38 activity during osteoblast differentiation and function, and emphasize the triggers of this MAPK.

• MAP kinase
• bone development
• bone homeostasis
• cell differentiation
• cell signaling
• osteoblast
• p38

The role of keratinocyte growth factor (KGF) in human umbilical cord-derived mesenchymal stem cell (hUC-MSC) differentiation remains unknown. Building on previous work, the authors found KGF expression in sweat gland-like cells (SGCs) and determined that recombinant human KGF could induce hUC-MSC differentiation into SGCs. These differentiated SGCs were applied to a mouse burn model and sweat glands were regenerated. These cells may have potential therapeutic application for regeneration of destroyed sweat glands and injured skin.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have higher proliferation potency and lower immune resistance than human bone marrow MSCs and can differentiate into various functional cells. Many regulatory factors, including keratinocyte growth factor (KGF), are involved in the development of skin and cutaneous appendages. Although KGF is important in wound healing, the role of KGF in hUC-MSC differentiation remains unknown. In our previous work, we found the mixing medium (nine parts of basic sweat-gland [SG] medium plus one part of conditioned heat-shock SG medium) could induce hUC-MSC differentiation to sweat gland-like cells (SGCs). In this study, we further improved the inducing medium and determined the effects of KGF in hUC-MSC differentiation. We found KGF expression in the SGCs and that recombinant human KGF could induce hUC-MSC differentiation into SGCs, suggesting KGF plays a pivotal role in promoting hUC-MSC differentiation to SGCs. Furthermore, the SGCs differentiated from hUC-MSCs were applied to severely burned skin of the paw of an in vivo severe combined immunodeficiency mouse burn model. Burned paws treated with SGCs could regenerate functional sparse SGs 21 days after treatment; the untreated control paws could not. Collectively, these results demonstrated that KGF is a critical growth factor for SGC differentiation from hUC-MSCs and the differentiated SGCs from hUC-MSCs may have a potential therapeutic application for regeneration of destroyed SGs and injured skin.

There is growing evidence demonstrating a potential therapeutic application of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in injured skin. In the current study, conditioned media and chemically defined media with recombinant human keratinocyte growth factor (KGF) could induce hUC-MSC differentiation into sweat gland-like cells (SGCs). Moreover, the differentiated SGCs from hUC-MSCs could regenerate functional sparse sweat glands in a mouse burn model, which provides further insight into the mechanisms of the role of KGF and a potential therapeutic application of differentiated SGCs for regeneration of destroyed sweat glands and injured skin.

• Burns
• Mesenchymal stem cell
• Sweat gland
• Tissue regeneration
• Transdifferentiation
• Umbilical cord
• Wharton’s jelly

• Animals
• Burns/metabolism
• Burns/therapy
• Cell Differentiation/drug effects
• Fetal Blood/metabolism
• Fibroblast Growth Factor 7/metabolism
• Fibroblast Growth Factor 7/pharmacology
• Heterografts
• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, SCID
• Skin/metabolism
• Sweat Glands/cytology
• Sweat Glands/metabolism

• R21 HL096007 NHLBI NIH HHS
• HL096007 NHLBI NIH HHS

• Bone healing
• Metabolic bone disease
• TNF-α

• Alcohol Drinking
• Animals
• Bone and Bones/pathology
• Diabetes Mellitus/physiopathology
• Female
• Fracture Healing
• Fractures, Bone/physiopathology
• Fractures, Bone/therapy
• Humans
• Inflammation
• Interleukin-1beta/physiology
• Mesenchymal Stem Cells/cytology
• Mice
• Obesity/physiopathology
• Osteogenesis/physiology
• Osteoporosis/physiopathology
• Osteoporosis, Postmenopausal/physiopathology
• Tumor Necrosis Factor-alpha/physiology

• Dendritic cells
• IDO
• IFN-γ
• Mesenchymal stem cells
• T cells
• TNF-α

• Computed tomography
• Hip fracture
• Muscle composition
• aged.

• Alpha6 Integrin
• Mammalian target of rapamycin
• Mesenchymal Stem Cells
• TNFalpha
• Tissue transglutaminase

• Actin
• Collagen 2α1
• Human serum albumin
• Mesenchymal stem cell
• Osteoarthritis
• PRAS40

• Bone Marrow Cells/drug effects
• Cell Differentiation/drug effects
• Clinical Trials, Phase III as Topic
• Hematopoietic Stem Cells/drug effects
• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/drug effects
• Molecular Weight
• Osteoarthritis/pathology
• Osteoarthritis/therapy
• Proteomics
• Serum Albumin/pharmacology
• Signal Transduction

• Aged
• Computed tomography
• Hip fracture
• Muscle composition

We investigated the effects of cytokines and chemokines and their associated signaling pathways on mesenchymal stem cell migration after spinal cord injury, to determine their roles in the curative effects of mesenchymal stem cells. This study reviewed the effects of tumor necrosis factor-α, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, basic fibroblast growth factor, insulin like growth factor-1, stromal cell-derived factor and monocyte chemoattractant protein-1, 3 during mesenchymal stem cell migration to damaged sites, and analyzed the signal transduction pathways involved in their effects on mesenchymal stem cell migration. The results confirmed that phosphatidylinositol 3-kinase/serine/threonine protein kinases and nuclear factor-κB play crucial roles in the migration of mesenchymal stem cells induced by cytokines and chemokines.

• chemokine
• cytokine
• mesenchymal stem cells
• migration
• neural regeneration
• signaling pathway
• spinal cord injury

La breaks the balance between osteogenesis and adipogenesis of MSCs through phosphorylating Smad1/5/8 to activate the BMP signaling pathway.

According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

• Mesenchymal stem cells
• Immunomodulation
• Cytokines
• Chemokines
• Dendritic cells