Growth Factor Secretion Research Articles

Aging-related decrease of histone methyltransferase SUV39H1 in adipose-derived stem cells enhanced SASP

Aging-related diseases are closely associated with the state of inflammation, which is known as “inflammaging.” Senescent cells are metabolically active, as exemplified by the secretion of inflammatory cytokines, chemokines, and growth factors, which is termed the senescence-associated secretory phenotype (SASP). Epigenetic regulation, especially the structural regulation of chromatin, is closely linked to the regulation of SASP. In our previous study, the suppressor of variegation 3–9 homolog 1 (SUV39H1) was elucidated to interact with Lhx8 and determine the cell fate of mesenchyme stem cells. However, the function of SUV39H1 during aging and the underlying mechanism of its epigenetic regulation remains controversial. Therefore, the C57BL/6 J CAG-Cre; SUV39H1fl/fl knockout mice and irradiation-induced cellular senescence model were built in this study to deepen the understanding of epigenetic regulation by SUV39H1 and its relation to SASP. In vivo and in vitro studies demonstrated that SUV39H1 decreased with aging and served as an inhibitor of SASP, especially IL-6, MCP-1, and Vcam-1, by altering H3K9me3 enrichment in their promoter region. These results provide new insights into the epigenetic regulation of SASP.

P-402 Inhibition of proline production by stromal cells negatively impacts myeloma tumor growth by reducing cytokine and growth factor secretion

P-402 Inhibition of proline production by stromal cells negatively impacts myeloma tumor growth by reducing cytokine and growth factor secretion

Continuity of care in acromegaly: Detecting and managing recurrence after surgical intervention

Acromegaly is a rare disease being followed up by primary care team. It is usually caused by pituitary adenoma and the treatment would be resection of the tumour. But is surgical intervention the end of treatment for acromegalic patient? This case highlighted the continuity of care in a 65-year old gentleman who had been diagnosed acromegaly since the age of 31. He had undergone a transseptal transsphenoidal resection of his pituitary adenoma when he was 45-year-old. Postoperatively, there were still residual growth hormone (GH) and insulin like growth factor (IGF-1) secretions. However, during 20 years follow up after operation, despite the increasing level of GH and IGF-1, the management of acromegaly were neglected as the focus of treatment were shifted towards his other medical problem, which is diabetes and atrial fibrillation. During his latest follow up, his complaint of unspecified headache and expressed his worry regarding the recurrence of his condition. Repeated GH level showed an increase in its level and postulated the possibility of recurrent acromegaly. This case emphasizes the important of recognizing the level of GH and IGF-1 after surgical intervention in order to detect recurrence acromegaly by primary care and early referral to endocrine team.

Rimonabant and Cannabidiol Rewrite the Interactions between Breast Cancer Cells and Tumor Microenvironment.

The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading. Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME. Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts. In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming. The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.

Neurotrophic neolignans of Pinus koraiensis twigs

Four undescribed neolignan analogs, together with eight known compounds, were isolated from the twigs of Pinus koraiensis (Korean pine). The chemical structure of the isolated compounds was determined through extensive spectroscopic analysis and chemical method. Their relative and absolute configurations were assigned through a well-established empirical rule and electronic circular dichroism (ECD) analysis, respectively. Four compounds (3 and 9–11) at 20 μM concentration showed significant neurotrophic effect by inducing nerve growth factor (NGF) secretion in C6 cells with the stimulation levels a range of 140.82 ± 4.62% to 160.04 ± 11.04%. Additionally, the result indicated that the glycosylation of neolignan led to an improvement in neurotrophic activity compared to their aglycone form. A compound (7) inhibited nitric oxide production with an IC50 value of 31.74 μM in LPS-activated BV2 cells.

Hipoxia modulates the secretion of growth factors of human umbilical cord-derived mesenchymal stem cells.

Mesenchymal stem cell (MSC) has great potential as therapies due its ability to regenerate tissue damage and promote tissue homeostasis. Preconditioning of MSC in low oxygen concentration has been shown to affect the therapeutic potential of these cells. This study aimed to compare the characteristic and secretion of trophic factors of MSCs cultured under hypoxia and normoxia. MSCs were isolated from Wharton's jelly of human umbilical cord (UC) tissue by explant method and characterized by flow cytometry. Following 24 h of CoCl2-induced hypoxic culture, the viability and metabolic activity of MSC were analyzed by trypan blue exclusion test and methyl thiazolyl tetrazolium (MTT) assay, respectively. The secretion of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) was assessed in conditioned medium using enzyme-linked immunosorbent assay (ELISA) method. Flow cytometry analysis showed >99% of the population of MSCs cells were positive for CD73 and CD90 and > 62% were positive for CD105. While the cell viability of MSC was not affected by hypoxic cultured condition, the metabolic activity rate of these cells was decreased under hypoxic conditioning. In line with reduced metabolic activity, hypoxic human UC-derived MSC produced less HGF than normoxic counterpart. Compared to normoxic MSC, hypoxic preconditioned MSC secreted higher level of VEGF in the conditioned medium (p < 0.05). Hypoxia decreased the metabolic activity of MSCs associated with the modulation of HGF and VEGF secretions. It is suggested that hypoxia may also affect the therapeutic capacity of MSC cells.

The role of cannabinoid CB1 receptors in the antinociceptive and reparative actions of mesenchymal stem cells in rats with peripheral neuropathic pain.

Mesenchymal stem cells (MSCs) can produce antinociceptive and reparative effects. Presumably, the MSCs-induced antinociception may be partly due to the involvement of the endocannabinoid system. The study aimed to evaluate the antinociceptive and reparative effects of adipose-derived MSCs (ADMSCs) upon pharmacological modulation of cannabinoid CB1 receptor in peripheral tissues or on ADMSCs' membranes in a rat model of peripheral neuropathy. ADMSCs were injected into the area of rat sciatic nerve injury (i) with no additional treatments, (ii) at the tissue CB1 receptor activation by endogenous agonist anandamide (AEA) or blockade with a selective AM251 antagonist; and (iii) preincubated with AEA or AM251. The evaluation of CB1 receptor activity involved analyzing nociceptive responses, gait parameters, and histology. Transplantation of ADMSCs upon activation of CB1 receptors, both on AMSCs' membranes or in the area of nerve injury, accelerated the analgesia and recovery of dynamic gait parameters, abolished static gait disturbances, and promoted the fastest nerve regeneration. Only blockade of CB1 receptors on ADMSCs shortened ADMSCs-induced analgesia and decreased the number of preserved nerve fibers. CB1 receptors on ADMSCs significantly contribute to their pain-relieving and tissue-repairing capabilities by stimulating the growth factors secretion and suppressing the release of pro-inflammatory cytokines. Peripheral CB1 receptors do not significantly influence ADMSC-induced antinociception.

Transplantable stem cell nanobridge scaffolds for accelerating articular cartilage regeneration

Microfracture technique for treating articular cartilage defects usually has poor clinical outcomes due to critical heterogeneity and extremely limited in quality. To improve the effects of current surgical technique (i.e., microfracture technique), we propose the transplantable stem cell nanobridge scaffold, acting as a protective bridge between host tissue and defected cartilage as well as microfracture-derived cells. Nanobridge scaffolds have a sophisticated nanoaligned structure with freestanding and flexible shapes for imposing direct structural guidance to cells including transplanted stem cells and host cells, and it can induce not only chondrocyte migration but also stem cell differentiation, maturation, and growth factor secretion. The transplantable stem cell nanobridge scaffold is capable of reconstructing the defected cartilage with homogeneous architecture and highly enhanced adhesive stress similar with native cartilage tissue by the synergistic effects of stem cells-based chondro-induction and nanotopography-based chondro-conduction. Our findings demonstrate a significant advancement in the traditional treatment technique by using a nanoengineered tool for achieving successful cartilage regeneration.

The context-dependent role of the Na+/Ca2+-exchanger (NCX) in pancreatic stellate cell migration

Pancreatic stellate cells (PSCs) that can co-metastasize with cancer cells shape the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) by producing an excessive amount of extracellular matrix. This leads to a TME characterized by increased tissue pressure, hypoxia, and acidity. Moreover, cells within the tumor secrete growth factors. The stimuli of the TME trigger Ca2+ signaling and cellular Na+ loading. The Na+/Ca2+ exchanger (NCX) connects the cellular Ca2+ and Na+ homeostasis. The NCX is an electrogenic transporter, which shuffles 1 Ca2+ against 3 Na+ ions over the plasma membrane in a forward or reverse mode. Here, we studied how the impact of NCX activity on PSC migration is modulated by cues from the TME. NCX expression was revealed with qPCR and Western blot. [Ca2+]i, [Na+]i, and the cell membrane potential were determined with the fluorescent indicators Fura-2, Asante NaTRIUM Green-2, and DiBAC4(3), respectively. PSC migration was quantified with live-cell imaging. To mimic the TME, PSCs were exposed to hypoxia, pressure, acidic pH (pH 6.6), and PDGF. NCX-dependent signaling was determined with Western blot analyses. PSCs express NCX1.3 and NCX1.9. [Ca2+]i, [Na+]i, and the cell membrane potential are 94.4 nmol/l, 7.4 mmol/l, and − 39.8 mV, respectively. Thus, NCX1 usually operates in the forward (Ca2+ export) mode. NCX1 plays a differential role in translating cues from the TME into an altered migratory behavior. When NCX1 is operating in the forward mode, its inhibition accelerates PSC migration. Thus, NCX1-mediated extrusion of Ca2+ contributes to a slow mode of migration of PSCs.

Oncogenesis Induced by Polyomavirus (BKV)

Polyomavirus BK (BKV) or human Polyomavirus is an icosahedral, non-enveloped virus classified under the Polyomaviridae family. The oncogenic properties of BKV belong to both an early domain and late domains. BKV encodes important Tag proteins such as LTAg and STAg “Tumour antigen; Tag. They succeeded in altering and stimulating infected cells to uncontrolled proliferation experimentally in both culture cell and animal models. This study aims to summarize the important oncogenic pathway that BKV used to initiate tumor. Both BKV proteins LTAg and STAg interfere with many cellular pathways/proteins such as retinoblastoma proteins, PP2A, P53, MAP kinases pathway, tumor suppressor proteins, telomerase, endothelial growth factor, leading to uncontrol of cell proliferation and apoptosis. This study concluded that stimulation of cell growth and secretion of extra endothelial growth factor in the absence of antiapoptotic proteins increases BKV proteins to mediate cancer development.

Mathematical and numerical analyses of cellular, molecular and angiogenic parameters of a rat skin wound healing model.

The inflammatory phase is an important event in the skin wound healing process. The deposition of granulation tissue in the wound bed and the rebuilding of the vascular network occur as inflammation diminishes. An angiogenic component in the formation of granulation tissue is the secretion of vascular endothelial growth factor, which assists in the chemotaxis, proliferation, and replication of fibroblasts. In this paper, we develop a mathematical model of skin wound healing angiogenic factors based on inflammatory cells (macrophages and neutrophils) and mediators (interleukin 6 and interleukin 10). We highlight the importance of this process in vascular endothelial growth factor release and in the formation of new capillary tips. We used a mathematical model of partial differential equations based on the reaction-diffusion-advection equations. In order to calibrate the parameters, we considered an in vivo model composed by four treatments: hydroalcoholic extract and oil-resin of Copaifera langsdorffii at 10% concentration, collagenase, and Lanette cream. Using the laboratory data for the wound edge, our mathematical model estimated the values of vascular endothelial growth factor concentration, and tips density in the center of the wound with a maximum error of 2.9%, and predicted healing time required for each treatment. The region of viability for the parameters, in the proposed model, was found through numerical simulations from the Interleukin 6 and 10 dysregulation and we obtained that, among the parameters analyzed, the greatest influencer in the dynamics of the system is the one, which represents the production of Interleukin 10 during phagocytosis.

Different responses of the MIO‑M1 Mueller cell line to angiotensin II under hyperglycemic or hypoxic conditions.

Members of the renin-angiotensin aldosterone system (RAAS) are expressed by various retinal tissues including Mueller glial cells. As the RAAS is hypothesized to play an important role in the pathogenesis of diseases that threaten vision, such as diabetic macular edema or retinal vein occlusion, the possible changes induced by exposure of the human cell line MIO-M1, an established model of Mueller cells, to angiotensin II or aldosterone for 6 h under hypoxic and/or hyperglycemic conditions were investigated. The mRNA expression levels of the members of the RAAS were assessed by reverse transcription-quantitative PCR, and the secretion of cytokines was assessed by ELISA. Under hyperglycemic conditions, the mRNA expression levels of the angiotensin-converting enzyme 2 (ACE2), angiotensin II receptors, AT1 and AT2, and the receptor of angiotensin (1-7) MAS1 were significantly higher after exposure to angiotensin II, and the expression of ACE2, AT2, and IL-6 (a marker of inflammation) was significantly increased after treatment with aldosterone; the expression of the other targets investigated remained unchanged. Significantly more IL-6 was secreted by MIO-M1 cells exposed to hyperglycemia and angiotensin. When cells were cultured in a hypoxic environment, additional treatment with aldosterone significantly increased the mRNA expression levels of ACE, but significantly more ACE2 mRNA was expressed in the presence of angiotensin II. Under hypoxic plus hyperglycemic conditions, significantly less ACE but more AT2 was expressed after treatment with angiotensin II, which also led to strongly elevated expression of IL-6. The mRNA expression levels of the angiogenic growth factor VEGF-A and secretion of the encoded protein were notably increased under hypoxic and hypoxic plus hyperglycemic conditions, irrespective of additional treatment with angiotensin II or aldosterone. These findings suggest that angiotensin II induces a pro-inflammatory response in MIO-M1 cells under hyperglycemic conditions despite activation of the counteracting ACE2/MAS1 signaling cascade. However, hypoxia results in an increased expression of angiogenic VEGF-A by these cells, which is not altered by angiotensin II or aldosterone.

Abstract P2042: Linking Extracellular Matrix Stiffness With Cardiomyocyte Structure And Function

The composition and organization of the extracellular matrix (ECM) provides cues to myocardial cells that direct normal function and responses to stress. However, little is known about how exactly a change in environmental tension leads to alterations in cardiomyocyte cell size and contractile force. Collagen I comprises the majority of cardiac ECM where it is crosslinked and matured by the lysyl oxidase (LOX) family of enzymes that includes LOX and LOX-like (LOXL) proteins. LOX and LOXLs are frequently upregulated in the heart after injury, and their inhibition has been shown to alleviate increases in tissue stiffness. Cardiac injury models result in activation and recruitment of many cells that secrete growth factors and modify the ECM, which makes it difficult to address specifically how cardiomyocytes are responding to changes in matrix tension alone. Therefore, we utilized LOX or LOXL overexpression as a tool to stiffen the ECM in the absence of pathophysiologic injury and paracrine factors. Transgenic overexpression of LOX increases myocardial stiffness and results in mild cardiac dysfunction by 9 months of age. While younger adult mice do not display a phenotype at baseline, they have an exaggerated response to pressure overload hypertrophy. In a different set of experiments, adeno-associated viruses (AAV9) for LOXL1, -2, or -3 were administered to mouse pups via cardiac injection at perinatal day 7. By 12 weeks of age, LOXL1 overexpression leads to cardiac hypertrophy with preserved ejection fraction, while increased LOXL2 or LOXL3 results in decreased cardiac function (each with differential patterns of myocardial fibrosis). Ongoing studies are assessing how these functional changes are associated with alterations in tissue stiffness and cardiomyocyte behavior. Determining how cardiomyocytes respond to alterations in the physical properties of the ECM will improve our understanding of the etiology of progressive cardiomyopathies and fibrosis.

Abstract P2106: Transforming Growth Factor β-dependent Regulation Of Cardiomyocyte Maturation

Transforming growth factor β (TGFβ) is a secreted growth factor that is sequestered to the ECM as a latent complex and released in response to cardiac stress. Once released, TGFβ is required for conversion of quiescent fibroblasts to myofibroblasts that support cardiac repair and fibrosis through production of ECM components. While these functional features of TGFβ are well known, the fibroblast-independent effector functions of TGFβ in the heart are unknown. We hypothesized that TGFβ is a critical ECM-cell cross talk mediator in the heart whereby cardiomyocyte -generated TGFβ communicates with fibroblasts to program the composition and stability of the ECM in a reinforcing feedback network. We found that deletion of TGFβ ligands ( Tgfb1 , Tgfb2 , and Tgfb3 ) from cardiomyocytes with an α-MHC-Cre transgene ( Tgfb123 fl/fl -αMHC-Cre ), but not a fibroblast-specific targeted allele ( Tgfb123 fl/fl -Tcf21-MCM ), results in cardiac dysfunction. These results suggest that cardiomyocytes (CMs) are the predominant source of TGFβ in the heart at baseline and that perhaps celltypes beyond the fibroblast were also involved. Interestingly, fibroblast numbers and ECM deposition are increased in Tgfb123 fl/fl -αMHC-Cre hearts and with acute injury hearts from these mice produce shorter, disorganized collagen fibers. Gene expression profiling of Tgfb123 fl/fl -αMHC-Cre hearts at 6 weeks of age demonstrates defective cardiomyocyte maturation. Indeed, Tgfb123 fl/fl -αMHC-Cre hearts are dysmorphic at neonatal day 1 and cardiomyocytes from these hearts remain in cell cycle for a longer duration with greater levels of mononucleation. However, deleting TGFβ receptors I/II or Smad2/3 from CMs does not recapitulate this phenotype suggesting that TGFβ is not driving CM maturation in an autocrine manner. Instead, these findings indicate that TGFβ functions as a critical cross-talk mediator to fibroblasts to establish proper ECM organization and content that drives CM maturation.

Abstract P3162: Evaluating Cargo And Cardioprotective Effects Of Extracellular Vesicles From Human Right Atrial Appendage Mesenchymal Cells

Our team has previously shown the isolation and culture of a mesenchymal cell population from the right atrial appendage (RAA) of living human donor tissues. The cells are CD44/105/166 + , CD45/19/11b - and secrete growth factors (including VEGF and IGF-1) comparable to BM-MSCs. Their secretome preserved EF% and dP/dTmax in a mouse MI model and stimulated angiogenesis in a mouse limb ischemia model. In the current study, we specifically investigated using these cell-derived extracellular vesicles (EV) as a therapeutic. First, we validated our isolation technique and profiled EV miRNA cargo using PCR arrays. We then assessed the ability of EVs to protect human cardiomyocytes in a hypoxic (1% O2) hiPSC-CM model. Lastly, we used RNA-seq to compare the transcriptome of EV-treated hiPSC-CMs against hypoxic and normoxic controls. Results confirmed isolation of high purity EVs, showing (by cryoEM) ~120 nm bilayer membrane-bound vesicles, positive for CD81, CD63, ALIX, TSG101 and other EV markers (by antibody array). In the EV cargo we identified 363 known miRNAs present in 3 donor cell isolates, including hsa-miR-21-5p, -202-5p, -1260a and -125b. Target prediction of the most abundant miRNAs ranked GO:0010667 “negative regulation of cardiac muscle cell apoptotic process” as highly significant (26.3%, P = 1.6 x10 -8 ), as well as other predicted pathways related to angiogenesis, cardiac development and regulation of inflammation. A single, transient, treatment of donor EVs (66 ng EV protein/μl) reduced LDH leakage from hypoxic hiPSC-CMs, preserved morphology, and increased viability at 48 hrs and 7 days after injury. RNA-seq of the EV-treated hiPSC-CMs revealed strong upregulation of pathways related to PI3k-akt, calcium signaling and ECM binding compared to hypoxic hiPSC-CMs with vehicle control. We are currently validating key RNA-seq results. In conclusion, we analyzed and confirmed cardioprotective properties of EVs derived from human RAA samples using a human model system. Combined with our published animal studies, these data indicate that this cell population is a clinically-relevant source of donor cells for cardiac cell therapy. The EVs are also an attractive cell-free potential therapeutic option.

The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy.

Human leukocyte antigen-G (HLA-G) is a non-classical human major histocompatibility complex (MHC-I) molecule with the membrane-bound and soluble types. HLA-G is primarily expressed by extravillous cytotrophoblast cells located at the maternal-fetal interface during pregnancy and is essential in establishing immune tolerance. This review provides a comprehensive understanding of the multiple molecular mechanisms by which HLA-G regulates the immune function of NK cells. It highlights that HLA-G binds to microRNA to suppress NK cell cytotoxicity and stimulate the secretion of growth factors to support fetal growth. The interactions between HLA-G and NK cells also activate senescence signaling, promoting spiral artery remodeling and maintaining the balance of maternal-fetal immune responses. In addition, HLA-G can inhibit the function of decidual T cells, dendritic cells, and macrophages. Overall, the interaction between trophoblast cells and immune cells mediated by HLA-G plays a crucial role in understanding immune regulation at the maternal-fetal interface and offers insights into potential treatments for pregnancy-related diseases.

The Involvement of Progranulin for α-Synuclein Reduction through Autolysosome Formation.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms and neuropathological features, such as loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein (α-Syn). Progranulin (PGRN) is a secreted growth factor that exhibits anti-inflammatory properties and regulates lysosomal function. Although autophagy-lysosome pathway is the main degradative pathway for α-Syn, the molecular mechanistic relationship between PD and PGRN remains unclear. In this study, we investigated the role of PGRN in PD pathology. PGRN protein expression in striatum was increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Intracerebroventricular (i.c.v.) administration of PGRN ameliorated the decrease in expression of tyrosine hydroxylase, a dopaminergic neuron marker, in MPTP-treated mice. Furthermore, i.c.v. administration of PGRN ameliorated 6-hydroxydopamine-induced motor deficits. In SH-SY5Y human neuroblastoma cells, 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, increased α-Syn expression. In contrast, PGRN ameliorated MPP+-induced increase in α-Syn expression. Although PGRN decreased the levels of autophagy-related proteins Sequestosome-1 (p62) and MAP1LC3 (LC3)-II, PGRN did not influence the phosphorylation of AMP-activated protein kinase and mechanistic target of rapamycin, which are also proteins that regulate autophagy. Immunostaining analysis showed that PGRN ameliorated MPP+-induced increase of LC3 puncta, indicator of autophagosome, and co-localization of LC3 and α-Syn. The DALGreen assay showed that PGRN ameliorated MPP+-induced decreasing trend of autolysosomes. These results suggest that PGRN participates in α-Syn degradation via acceleration of the autophagy-lysosome pathway and is a potential therapeutic target for PD.

Chitosan based macromolecular hydrogel loaded total glycosides of paeony enhances diabetic wound healing by regulating oxidative stress microenvironment

Oxidative stress microenvironment caused by reactive oxygen species (ROS) accumulation seriously hinders wound healing in diabetes, which brings great burden to global health. Various wound dressings on the market focus on delivering active substances to promote wound healing in diabetes. However, the complex pathological microenvironment of diabetic wounds often leads to the inactivation of delivery factors, which often leads to treatment failure, and thus, emerging therapeutic approaches are urgently needed. In this study, a macromolecular hydrogel synthesized by crosslinking N-carboxyethyl chitosan, hyaluronic acid-aldehyde, and adipic acid dihydrazide, with self-healing and injectable abilities was used to deliver total glycosides of paeony (TGP). The TGP incorporated hydrogel could obviously induce fibroblasts proliferation and secretion of various extracellular matrix proteins and growth factors, induce migration and angiogenesis of vein endothelial cells, and enhance macrophages polarization to M2 phenotype by eliminating accumulated ROS. In diabetic wound models, the ROS-scavenging hydrogel efficiently enhanced proliferation, re-epithelialization, collagen deposition, as well as angiogenesis in the wound area. Besides, the dressing induced the macrophages polarization from M1 phenotype (pro-inflammatory) to M2 phenotype (anti-inflammatory) and decreased the levels of inflammatory cytokines, thereby enhancing the diabetic wound healing. The wounds treated with TGP incorporated hydrogel almost completely healed 16 days after treatment. However, the residual wound areas in the groups of Con, INTRA, and Gel are 55.2 ± 4.6 %, 33.7 ± 6.5 %, and 34.9 ± 6.1 % on the 16th day, respectively. This hydrogel with pathological microenvironment improvement ability affords a novel therapeutic strategy for enhancing healing of chronic diabetic wound.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer's disease.

Recent studies have demonstrated that neuroplasticity, such as synaptic plasticity and neurogenesis, exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer's disease. Hence, promoting neuroplasticity may represent an effective strategy with which Alzheimer's disease can be alleviated. Due to their significant ability to self-renew, differentiate, and migrate, neural stem cells play an essential role in reversing synaptic and neuronal damage, reducing the pathology of Alzheimer's disease, including amyloid-β, tau protein, and neuroinflammation, and secreting neurotrophic factors and growth factors that are related to plasticity. These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain. Consequently, neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer's disease and other neurodegenerative diseases. In this review, we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer's disease in the clinic.

EGF-expressed human mesenchymal stem cells inhibit collagenase1 expression in keratinocytes

Mesenchymal stem cells (MSCs) repair tissue injury by upregulating the paracrine secretion of cytokines and growth factors. Human MSC has been recognized as a promising therapeutic material for treatment of various human diseases. Even though the effect of epidermal growth factor (EGF) has been well investigated, the synergetic effect of EGF and MSC has not been studied. Therefore, we expect our basic study to contribute to developing new therapeutic reagents for skin diseases or innovative cosmetics. In this study, we examined the effect of human epidermal growth factor-transfected MSCs (hEGF MSCs) on human keratinocyte HaCaT cell proliferation and the mechanisms that regulate matrix metalloproteinase (MMP)-1 expression in HaCaT cells. To identify the hEGF plasmid and its transfection into MSCs, we performed gel electrophoresis and quantitative PCR. Proliferation and migration of HaCaT cells were examined using water Soluble Tetrazolium (WST-1) and wound-healing assays, respectively. Zymography was performed to investigate the correlation between hEGF MSC-conditioned medium (CM)-treated HaCaT cells and MMP-1 expression. We found that cell proliferation and wound-healing rates were increased in hEGF MSC-CM-treated HaCaT cells compared to those in MSC-CM-treated cells, and conversely collagenase activity was decreased. The mRNA and protein levels of MMP-1 were also decreased in hEGF MSC-CM-treated HaCaT cells. 2-DE analysis showed that the expression of carboxypeptidase, which promotes growth factors and wound healing, was increased in hEGF MSC-CM-treated HaCaT cells. Finally, western blot was used to determine whether MMP-1 expression was reduced via the mitogen-activated protein kinase (MAPK) pathway; the results showed that the levels of MAPK pathway-related proteins (pErk, pJNK, and p-p38) and the levels of transcription factors (pCREB, NFκB, and p-c-Fos) were decreased. In addition, pAkt expression was found to be elevated. The results of our study suggest that hEGF MSCs promote cell proliferation and reduce MMP-1 expression via the MAPK pathway in human keratinocyte HaCaT cells.