ERK signaling expands mammalian cortical radial glial cells and extends the neurogenic period.

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we report that fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces bone morphogenic protein 7 (Bmp7) expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and Sonic Hedgehog (SHH) signaling mutually inhibit each other in cortical RG cells. We provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We propose that the expansion of the mammalian cortex, notably in human, is driven by the ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the relatively short cortical neurogenic period in mice is partly due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.

Bmp7 drives proximal tubule expansion and determines nephron number in the developing kidney.

The mammalian kidney is composed of thousands of nephrons that are formed through reiterative induction of a mesenchymal-to-epithelial transformation by a population of nephron progenitor cells. The number of nephrons in human kidneys ranges from several hundred thousand to nearly a million, and low nephron number has been implicated as a risk factor for kidney disease as an adult. Bmp7 is among a small number of growth factors required to support the proliferation and self-renewal of nephron progenitor cells, in a process that will largely determine the final nephron number. Once induced, each nephron begins as a simple tubule that undergoes extensive proliferation and segmental differentiation. Bmp7 is expressed both by nephron progenitor cells and the ureteric bud derivative branches that induce new nephrons. Here, we show that, in mice, Bmp7 expressed by progenitor cells has a major role in determining nephron number; nephron number is reduced to one tenth its normal value in its absence. Postnatally, Bmp7 also drives proliferation of the proximal tubule cells, and these ultimately constitute the largest segment of the nephron. Bmp7 appears to act through Smad 1,5,9(8), p38 and JNK MAP kinase. In the absence of Bmp7, nephrons undergo a hypertrophic process that involves p38. Following a global inactivation of Bmp7, we also see evidence for Bmp7-driven growth of the nephron postnatally. Thus, we identify a role for Bmp7 in supporting the progenitor population and driving expansion of nephrons to produce a mature kidney.

Cochlear tonotopy from proteins to perception.

A ubiquitous feature of the auditory organ in amniotes is the longitudinal mapping of neuronal characteristic frequencies (CFs), which increase exponentially with distance along the organ. The exponential tonotopic map reflects variation in hair cell properties according to cochlear location and is thought to stem from concentration gradients in diffusible morphogenic proteins during embryonic development. While in all amniotes the spatial gradient is initiated by sonic hedgehog (SHH), released from the notochord and floorplate, subsequent molecular pathways are not fully understood. In chickens, BMP7 is one such morphogen, secreted from the distal end of the cochlea. In mammals, the developmental mechanism differs from birds and may depend on cochlear location. A consequence of exponential maps is that each octave occupies an equal distance on the cochlea, a spacing preserved in the tonotopic maps in higher auditory brain regions. This may facilitate frequency analysis and recognition of acoustic sequences.

Evaluation of the Reparative Effect of Sinomenine in an Acetaminophen-Induced Liver Injury Model.

Due to its rising global prevalence, liver failure treatments are urgently needed. Sinomenine (SIN), an alkaloid from sinomenium acutum, is being studied for its liver-repair properties due to Acetaminophen (APAP) overdose. SIN's effect on APAP-induced hepatotoxicity in rats was examined histologically and biochemically. Three groups of 30 adult male Wistar rats were created: control, APAP-only, and APAP + SIN. Histopathological and biochemical analyses were performed on liver samples after euthanasia. SIN is significantly protected against APAP damage. Compared to APAP-only, SIN reduced cellular injury and preserved hepatocellular architecture. The APAP + SIN Group had significantly lower ALT, MDA, and GSH levels, protecting against hepatocellular damage and oxidative stress. SIN also had dose-dependent antioxidant properties. When examining critical regulatory proteins, SIN partially restored Sirtuin 1 (SIRT1) levels. While BMP-7 levels were unaffected, histopathological evidence and hepatocyte damage percentages supported SIN's liver-restorative effect. SIN protected and repaired rats' livers from APAP-induced liver injury. This study suggests that SIN may treat acute liver damage, warranting further research into its long-term effects, optimal dosage, and clinical applications. These findings aid liver-related emergency department interventions and life-saving treatments.

Omentin-1 drives cardiomyocyte cell cycle arrest and metabolic maturation by interacting with BMP7.

Mammalian cardiomyocytes (CMs) undergo maturation during postnatal heart development to meet the increased demands of growth. Here, we found that omentin-1, an adipokine, facilitates CM cell cycle arrest and metabolic maturation. Deletion of omentin-1 causes mouse heart enlargement and dysfunction in adulthood and CM maturation retardation in juveniles, including delayed cell cycle arrest and reduced fatty acid oxidation. Through RNA sequencing, molecular docking analysis, and proximity ligation assays, we found that omentin-1 regulates CM maturation by interacting directly with bone morphogenetic protein 7 (BMP7). Omentin-1 prevents BMP7 from binding to activin type II receptor B (ActRIIB), subsequently decreasing the downstream pathways mothers against DPP homolog 1 (SMAD1)/Yes-associated protein (YAP) and p38 mitogen-activated protein kinase (p38 MAPK). In addition, omentin-1 is required and sufficient for the maturation of human embryonic stem cell-derived CMs. Together, our findings reveal that omentin-1 is a pro-maturation factor for CMs that is essential for postnatal heart development and cardiac function maintenance.

Lead Decreases Bone Morphogenetic Protein-7 (BMP-7) Expression and Increases Renal Cell Carcinoma Growth in a Sex-Divergent Manner.

Both tissue and blood lead levels are elevated in renal cell carcinoma (RCC) patients. These studies assessed the impact of the subchronic lead challenge on the progression of RCC in vitro and in vivo. Lead challenge of Renca cells with 0.5 µM lead acetate for 10 consecutive passages decreased E-cadherin expression and cell aggregation. Proliferation, colony formation, and wound healing were increased. When lead-challenged cells were injected into mice, tumor size at day 21 was increased; interestingly, this increase was seen in male but not female mice. When mice were challenged with 32 ppm lead in drinking water for 20 weeks prior to tumor cell injection, there was an increase in tumor size in male, but not female, mice at day 21. To investigate the mechanism underlying the sex differences, the expression of sex hormone receptors in Renca cells was examined. Control Renca cells expressed estrogen receptor (ER) alpha but not ER beta or androgen receptor (AR), as assessed by qPCR, and the expression of ERα was increased in tumors in both sexes. In tumor samples harvested from lead-challenged cells, both ERα and AR were detected by qPCR, yet there was a significant decrease in AR seen in lead-challenged tumor cells from male mice only. This was paralleled by a plate-based array demonstrating the same sex difference in BMP-7 gene expression, which was also significantly decreased in tumors harvested from male but not female mice; this finding was validated by immunohistochemistry. A similar expression pattern was seen in tumors harvested from the mice challenged with lead in the drinking water. These data suggest that lead promotes RCC progression in a sex-dependent via a mechanism that may involve sex-divergent changes in BMP-7 expression.

High BMP7 expression is associated with poor prognosis in ovarian cancer.

Bone Morphogenetic Protein 7 (BMP7) is an extracellular signalling protein that belongs to the transforming growth factor-ß (TGF- ß) superfamily. Previous transcriptomic data suggested that BMP7 expression may be disrupted in ovarian carcinoma and may play an important role in the aggressiveness of the disease. However, the protein expression in patient tumours has not been well studied. The current study aimed to assess BMP7 protein expression in a large cohort of ovarian carcinoma patient tumour samples to establish its associations with different clinical endpoints. Ovarian carcinoma tissue samples from 575 patients who underwent surgery for different subtypes of ovarian cancer were used. BMP7 protein expression was analysed by immunohistochemistry using tissue microarray and full face tumour sections. High BMP7 expression is associated with aggressive ovarian cancer clinicopathological variables including advanced FIGO stage, high grade, residual disease and poor overall survival. Elevated cytoplasmic and nuclear BMP7 expression was significantly associated with advanced FIGO stage, high tumour grade, presence of residual tumours and high-grade serous carcinomas (p = 0.001, 0.005, 0.004, <0.001 and p < 0.001, <0.001, 0.002, 0.001 respectively). Increased cytoplasmic and nuclear BMP7 expression was also significantly associated with an adverse overall survival (p = 0.001 and 0.046 respectively). The study highlights the potential of BMP7 as a prognostic tool and as a potential novel target for ovarian cancer therapies to limit disease progression.

Protective effect of bone morphogenetic protein-7 induced differentiation of bone marrow mesenchymal stem cells in rat with acute spinal cord injury.

The principal aim of present study was to assess the therapeutic efficacy of bone morphogenetic protein-7 (BMP-7) induced differentiation of bone marrow mesenchymal stem cells (BMSCs) in a rat acute spinal cord injury (SCI) model. BMSCs were isolated from rats, and then divided into a control and a BMP-7 induction groups. The proliferation ability of BMSCs and glial cell markers were determined. Forty Sprague-Dawley (SD) rats were randomly divided into sham, SCI, BMSC, and BMP7 + BMSC groups (n = 10). Among these rats, the recovery of hind limb motor function, the pathological related markers, and motor evoked potentials (MEP) were identified. BMSCs differentiated into neuron-like cells after the introduction of exogenous BMP-7. Interestingly, the expression levels of MAP-2 and Nestin increased, whereas the expression level of GFAP decreased after the treatment with exogenous BMP-7. Furthermore, the Basso, Beattie, and Bresnahan (BBB) score reached 19.33 ± 0.58 in the BMP-7 + BMSC group at day 42. Nissl bodies in the model group were reduced compared to the sham group. After 42 days, in both the BMSC and BMP-7 + BMSC groups, the number of Nissl bodies increased. This is especially so for the number of Nissl bodies in the BMP-7 + BMSC group, which was more than that in the BMSC group. The expression of Tuj-1 and MBP in BMP-7 + BMSC group increased, whereas the expression of GFAP decreased. Moreover, the MEP waveform decreased significantly after surgery. Furthermore, the waveform was wider and the amplitude was higher in BMP-7 + BMSC group than that in BMSC group. BMP-7 promotes BMSC proliferation, induces the differentiation of BMSCsinto neuron-like cells, and inhibits the formation of glial scar. BMP-7 plays a confident role in the recovery of SCI rats.

BMP7 ameliorates intervertebral disc degeneration in type 1 diabetic rats by inhibiting pyroptosis of nucleus pulposus cells and NLRP3 inflammasome activity.

BACKGROUND: Accumulating evidence indicates that intervertebral disc degeneration (IDD) is associated with diabetes mellitus (DM), while the underlying mechanisms still remain elusive. Herein, the current study sought to explore the potential molecular mechanism of IDD in diabetic rats based on transcriptome sequencing data. METHODS: Streptozotocin (STZ)-induced diabetes mellitus type 1 (T1DM) rats were used to obtain the nucleus pulposus tissues for transcriptome sequencing. Next, differentially expressed genes (DEGs) in transcriptome sequencing data and GSE34000 microarray dataset were obtained and intersected to acquire the candidate genes. Moreover, GO and KEGG enrichment analyses were performed to analyze the cellular functions and molecular signaling pathways primarily regulated by candidate DEGs. RESULTS: A total of 35 key genes involved in IDD of T1DM rats were mainly enriched in the extracellular matrix (ECM) and cytokine adhesion binding-related pathways. NLRP3 inflammasome activation promoted the pyroptosis of nucleus pulposus cells (NPCs). Besides, BMP7 could affect the IDD of T1DM rats by regulating the inflammatory responses. Additionally, NPCs were isolated from STZ-induced T1DM rats to illustrate the effects of BMP7 on IDD of T1DM rats using the ectopic expression method. Both in vitro and in vivo experiments validated that BMP7 alleviated IDD of T1DM rats by inhibiting NLRP3 inflammasome activation and pyroptosis of NPCs. CONCLUSION: Collectively, our findings provided novel mechanistic insights for understanding of the role of BMP7 in IDD of T1DM, and further highlighted BMP7 as a potential therapeutic target for preventing IDD in T1DM.

BMP7 Attenuates Neuroinflammation after Spinal Cord Injury by Suppressing the Microglia Activation and Inducing Microglial Polarization Via the STAT3 Pathway.

Excessive activation of pro-inflammatory (M1) microglia phenotypes after spinal cord injury (SCI) disrupts tissue repair and increases the risk of secondary SCI. We previously reported that adeno-associated virus (AAV) mediated delivery of bone morphogenetic protein 7 (BMP7) promotes functional recovery after SCI by reducing oligodendrocyte loss and demyelination; however, little is known about the early effects of BMP7 in ameliorating neuroinflammation in the acute SCI phase. Herein, we demonstrate that treatment with recombinant human BMP7 (rhBMP7) suppresses the viability of LPS-induced HMC3 microglia cells and increases the proportion with the M2 phenotype. Consistently, in a rat SCI model, rhBMP7 decreases the activation of microglia and promotes M2 polarization. After rhBMP7 administration, the STAT3 signaling pathway was activated in LPS-induced HMC3 cells and microglia in spinal cord lesions. Furthermore, the levels of TNF-α and IL-1ß were significantly decreased in cell culture supernatants, lesion sites of injured spinal cords, and cerebrospinal fluid circulation after rhBMP7 administration, thus reducing neuron loss in the injured spinal cord and promoting functional recovery after SCI. These results provide insight into the immediate early mechanisms by which BMP7 may ameliorate the inflammation response to secondary SCI.

Effect of gamma and Ultraviolet-C sterilization on BMP-7 level of indigenously prepared demineralized freeze-dried bone allograft.

The presence of bone morphogenetic proteins in demineralized freeze-dried bone allograft (DFDBA) are responsible for developing hard tissues in intraosseous defects. The most common mode of sterilization of bone allografts, i.e., Gamma rays, have dramatic effects on the structural and biological properties of DFDBA, leading to loss of BMPs. Ultraviolet-C radiation is a newer approach to sterilize biodegradable scaffolds, which is simple to use and ensures efficient sterilization. However, UV-C radiation has not yet been effectively studied to sterilize bone allografts. This study aimed to compare and evaluate the effectiveness of Gamma and Ultraviolet-C rays in sterilizing indigenously prepared DFDBA and assess their effect on the quantity of BMP-7 present in the allograft. DFDBA samples from non-irradiated, gamma irradiated, and UV-C irradiated groups were tested for BMP-7 level and samples sterilized with gamma and UV-C rays were analysed for sterility testing. The estimated mean BMP-7 level was highest in non-irradiated DFDBA samples, followed by UV-C irradiated, and the lowest in gamma irradiated samples. Our study concluded that UV-C rays effectively sterilized DFDBA as indicated by negative sterility test and comprised lesser degradation of BMP-7 than gamma irradiation.

Assessment of BMP7, SMAD4, and CDH1 Expression Profile and Regulatory miRNA-542-3p in Eutopic and Ectopic Endometrium of Women with Endometriosis.

Alterations in the expression of numerous genes and the miRNAs that are recognized as their regulators in the endometrial cells of women with endometriosis may disrupt the intracellular signaling pathways associated with epithelial-mesenchymal transition (EMT). So far, the functional role of BMP7 in endometrial physiology has been confirmed, especially in the context of fertility, but the role of the activation of a specific mechanism operating through the BMP-SMAD-CDH1 axis in the formation of endometrial lesions remains unexplored. The aim of this study was to evaluate the expression profile of miR-542-3p and the EMT markers (BMP7, SMAD4, CDH1) in matched eutopic endometrium (EUE) and ectopic endometrium (ECE) samples from women with endometriosis in relation to healthy women. The levels of expression of the studied genes and miRNA in peripheral blood mononuclear cells (PBMCs) obtained from women diagnosed with endometriosis and those without the disease were also evaluated. Fifty-four patients (n = 54: with endometriosis-n = 29 and without endometriosis-n = 25) were included in the study. A comparative analysis of the relative mean expression values (RQ) of the studied mRNA and miRNA assessed by RT-qPCR demonstrated downregulation of BMP7, SMAD4, and CDH1 expression in ectopic lesions and upregulation in the eutopic endometrium compared with the control group. In the eutopic tissue of women with endometriosis, miR-542-3p expression was similar to that of the control but significantly lower than in endometrial lesions. We also confirmed a trend towards a negative correlation between miR-542-3p and BMP7 in ectopic tissue, and in PBMC, a significant negative correlation of miR-542-3p with further BMP signaling genes, i.e., SMAD4 and CDH1, was observed. These results indicate that the miRNA selected by us may be a potential negative regulator of BMP7-SMAD4-CDH1 signaling associated with EMT. The different patterns of BMP7, SMAD4, and CDH1 gene expression in ECE, EUE, and the control endometrium observed by us suggests the loss of the endometrial epithelium phenotype in women with endometriosis and demonstrates their involvement in the pathogenesis and pathomechanism of this disease.

BMP7 alleviates trigeminal neuralgia by reducing oligodendrocyte apoptosis and demyelination.

BACKGROUND: BMP7 has been shown to have neuroprotective effects and to alleviate demyelination. However, its role in trigeminal neuralgia (TN) has not been well investigated. The current study aims to determine whether BMP7 plays a role in demyelination, its effects on pain behaviors and mechanism of action in rats with TN. METHODS: We used an infraorbital-nerve chronic-constriction injury (ION-CCI) to establish a rat model of TN. Adeno-associated viruses (AAVs) were injected into the rats to upregulate or downregulate BMP7. The mechanical withdrawal thresholds (MWT) of the injured rats were detected using Von Frey filaments. The changes in expression levels of BMP7 and oligodendrocyte (OL) markers were examined by western blotting, quantitative real-time PCR, immunofluorescence, and transmission electron microscopy. RESULTS: The ION-CCI induced mechanical allodynia, demyelination, and loss of OLs with a reduction of BMP7. Short-hairpin RNA (shRNA)-BMP7 that inhibited BMP7 expression also caused mechanical allodynia, demyelination, and loss of OLs, and its mechanism may be OL apoptosis. Overexpressing BMP7 in the trigeminal spinal subnucleus caudalis(VC) with AAV-BMP7 relieved all three phenotypes induced by the CCI, and its mechanism may be alleviating OLs apoptosis. Two signal pathways associated with apoptosis, STAT3 and p65, were significantly downregulated in the VC after CCI and rescued by BMP7 overexpression. CONCLUSION: BMP7 can alleviate TN by reducing OLs apoptosis and subsequent demyelination. The mechanism behind this protection could be BMP7-mediated activation of the STAT3 and NF-κB/p65 signaling pathway and subsequent decrease in OL apoptosis. Importantly, our study presents clear evidence in support of BMP7 as a possible therapeutic target for the treatment of TN.

The expression of BMP, integrin, ZEB2 in ovarian high-grade serous carcinoma in relation with lymph node metastasis.

Ovarian cancer (OC) is clinically important because it is diagnosed late and has metastasis when it is diagnosed. Mortality risk increases 2.75 times in the presence of lymph node (LN) metastasis. During metastasis, many molecules including BMPs originated from stroma, and tumor cells participate through transcription factors and integrins for cytoskeleton regulation during cell migration. We hypothesized an inverse correlation between BMP2 and BMP7 along with changes in ZEB2, and integrin α5ß1 in high-grade OCs in relation to LN metastasis. The BMP2 immunoreactivity was strong along with strong ZEB2 and weak integrins' immunoreactivity in samples with LN metastasis. Strong immunoreactivity of BMP7 was accompanied by strong immunoreactivity of integrins in the samples without LN metastasis. Study results showed BMP2's strong positive immunoreactivity and weak BMP7 immunoreactivity in tumor cells with a significantly weak inverse correlation. This inverse correlation should be considered as both BMPs have different effects in the window of cancer progression and invasion.

Exogenous BMP7 administration attenuated vascular calcification and improved bone disorders in chronic uremic rats.

Vascular calcification is commonly observed in chronic kidney disease (CKD) and is associated with increased morbidity and mortality. This study examined whether exogenous BMP7 administration can modulate disturbed CKD-MBD in adenine-induced chronic uremic rats. After an adenine diet for 4 weeks, the animals were injected with BMP7 for 2 weeks. Biochemical data, kidney tissue, bony structure, and vascular calcification of the thoracic aorta were examined and compared. Reduced renal function, hyperphosphatemia, and hyperparathyroidism with low 1,25(OH)2 vitamin D levels were observed in the adenine group. MicroCT revealed reduced bone mineral density (BMD), decreased bone and tissue volume ratio (BV/TV), and decreased trabecular number with increased separation. Marked vascular calcification was observed in adenine-fed animals, and immunohistochemical analysis showed increased expression of BMP2, RUNX2, vitamin D receptor (VDR), and Pit1 in aortic tissue. Treatment with BMP7 was associated with reduced serum phosphate, intact parathyroid hormone, FGF23, sclerostin, and DKK1 levels. BMP7 administration was accompanied with improvements in BMD and BV/TV. The increase in BMP2, RUNX2, VDR, and Pit1 was reversed by BMP7. In conclusion, exogenous BMP7 administration improved hyperphosphatemia and hyperparathyroidism in adenine-induced CKD. This treatment also attenuated vascular calcification and modulated structural abnormalities in the skeletal system.

Verifying the outcomes of artesunate plus 595-nm PDL in hypertrophic scars via determining BMP-7 and Fas level in model rabbits.

BACKGROUND AND OBJECTIVES: Single-use of artesunate (ART) or 595-nm pulsed-dye laser (PDL) has proven clinical efficacy in the treatment of hypertrophic scars (HSs), yet little research has been done on the combined use of ART and PDL. Bone morphogenetic protein-7 (BMP-7) and Fas are recognized to be two important proteins in reducing scar formation. This study was designed to observe the effect of ART combined with 595-nm PDL in the treatment of HS in rabbit models, and investigate the effect of such protocol on the expression of BMP-7 and Fas in rabbit models. STUDY DESIGN/MATERIALS AND METHODS: Twenty-four New Zealand white rabbits were randomly divided into the control group, ART group, PDL group, and combined treatment (ART + PDL) group. ART was respectively applied to the ART group and combined treatment group. Treatment was once every 2-week for a total of three sessions for both groups. Animals in the PDL group were simply treated with 595-nm PDL. Then, hematoxylin & eosin and Van Gieson straining, immunohistochemical study, enzyme-linked immunosorbent assay (ELISA), Cell counting kit-8 test, western blot assay, and real-time polymerase chain reaction (RT-PCR) were carried out to observe the development of HS samples and expression of BMP-7 and Fas proteins in the sample tissues. RESULTS: After treatment, the scar samples grew lower and flatter, which was particularly evident in the combined treatment group, with notably inhibited fibroblast and collagen compared to other groups (p < 0.001). Western blot assay and RT-PCR demonstrated that the expression of BMP-7 was most increased in scar samples treated by ART + PDL. BMP-7 level was correspondingly and notably upregulated in treatment groups, especially in the ART + PDL group. In addition, relevant expression of Fas was also higher after treatment, especially in the ART + PDL group compared to either ART or 595-nm PDL group. The difference was significant among groups (p < 0.001). CONCLUSIONS: Combined use of ART and 595-nm PDL can inhibit HSs in rabbit models via inhibiting extra fibroblast and collagens. The potential mechanism may be involved in enhanced BMP-7 and Fas expression. Our observations may create an alternative therapeutic strategy for HSs in the clinic.

Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function.

BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the TGF-ß family that signal via the BMP receptor (BMPR) signaling cascade, distinct from canonical TGF-ß signaling. BMP downstream signaling is strongly induced within epidermal keratinocytes in cutaneous psoriatic lesions, and BMP7 instructs monocytic cells to acquire characteristics of psoriasis-associated Langerhans dendritic cells (DCs). Regulatory T (Treg)-cell numbers strongly increase during psoriatic skin inflammation and were recently shown to limit psoriatic skin inflammation. However, the factors mediating Treg-cell accumulation in psoriatic skin currently remain unknown. OBJECTIVE: We sought to investigate the role of BMP signaling in Treg-cell accumulation in psoriasis. METHODS: The following methods were used: immunohistology of patients and healthy controls; ex vivo models of Treg-cell generation in the presence or absence of Langerhans cells; analysis of BMP versus canonical TGF-ß signaling in DCs and Treg cells; and modeling of psoriatic skin inflammation in mice lacking the BMPR type 1a in CD11c+ cells. RESULTS: We here demonstrated a positive correlation between Treg-cell numbers and epidermal BMP7 expression in cutaneous psoriatic lesions and show that unlike Treg cells from healthy skin, a portion of inflammation-associated Treg cells exhibit constitutive-active BMP signaling. We further found that BMPR signaling licenses inflammation-associated Langerhans cell/DC to gain an enhanced capacity to promote Treg cells via BMPR-mediated CD25 induction and that this effect is associated with reduced skin inflammation. CONCLUSIONS: Psoriatic lesions are marked by constitutive high BMP7/BMPR signaling in keratinocytes, which instructs inflammatory DCs to gain enhanced Treg-cell-stimulatory activity. Locally secreted BMP7 can directly promote Treg-cell generation through the BMP signaling cascade.

Micro-environmental signals directing human epidermal Langerhans cell differentiation.

Human Langerhans cells (LC) can be generated ex vivo from hematopoietic precursor cells in response to cytokines and cell-membrane associated ligands. These in vitro differentiation models provided mechanistic insights into the molecular and cellular pathways underlying the development of this unique, epithelia-associated dendritic cell subset. Notably, the human epidermal microenvironment is fully sufficient to induce LC differentiation from hematopoietic progenitors. Hence, dissecting the molecular characteristics of the human epithelial/epidermal LC niche, and testing defined ligands for their capacity to induce LC differentiation, led to a refined molecular model of LC lineage commitment. During epidermal ontogeny, spatially and temporally regulated availability of TGF-ß family members cooperate with other keratinocyte-derived signals, such as E-cadherin and Notch ligands, for instructing LC differentiation. In this review, we discuss the signals known to instruct human hematopoietic progenitor cells and myelomonocytic cells to undergo LC lineage commitment. Additionally, the current methods for generation of large numbers of human LC-like cells ex vivo in defined serum-free media are discussed.

Overexpression of bone morphogenetic protein 7 reduces oligodendrocytes loss and promotes functional recovery after spinal cord injury.

Spinal cord injury (SCI), as a severe disease with no effective therapeutic measures, has always been a hot topic for scientists. Bone morphogenetic protein 7 (BMP7), as a multifunctional cytokine, has been reported to exert protective effects on the nervous system. The present study aimed to investigate the neuroprotective effect and the potential mechanisms of BMP7 on rats that suffered SCI. Rat models of SCI were established by the modified Allen' s method. Adeno-associated virus (AAV) was injected at T9 immediately before SCI to overexpress BMP7. Results showed that the expression of BMP7 decreased in the injured spinal cords that were at the same time demyelinated. AAV-BMP7 partly reversed oligodendrocyte (OL) loss, and it was beneficial to maintain the normal structure of myelin. The intervention group showed an increase in the number of axons and Basso-Beattie-Bresnahan scores. Moreover, double-labelled immunofluorescence images indicated p-Smad1/5/9 and p-STAT3 in OLs induced by BMP7 might be involved in the protective effects of BMP7. These findings suggest that BMP7 may be a feasible therapy for SCI to reduce demyelination and promote functional recovery.

SNHG16/miR-485-5p/BMP7 axis modulates osteogenic differentiation of human bone marrow-derived mesenchymal stem cells.

BACKGROUND: Osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) is crucial for bone formation and its dysfunction is reported to be linked to osteoporosis (OP). The present study aimed to probe the function of the long non-coding RNA small nucleolar RNA host gene 16 (SNHG16) with respect to modulating the osteogenic differentiation of hBMSCs. METHODS: SNHG16 expression in hBMSCs obtained from OP patients was measured by a quantitative real-time polymerase chain reaction (qRT-PCR). Gain-of-function and loss-of-function models of SNHG16 were established with hBMSCs. The expression of OP-related genes (ALP, OCN and OPN) in hBMSCs was determined by qRT-PCR and western blotting. StarBase, TargetScan7.2, miRDB and PicTar databases were used to predict the binding sites between SNHG16 and miR-485-5p, miR-485-5p and 3'-UTR of bone morphogenetic protein 7 (BMP7), respectively. A dual-luciferase reporter assay was used to determine the regulatory relationships between SNHG16 and miR-485-5p, miR-485-5p and 3'-UTR of BMP7, respectively. RESULTS: SNHG16 was remarkably down-regulated in hBMSCs obtained from patients with OP. Overexpression of SNHG16 promoted the osteogenic differentiation of hBMSCs, whereas knockdown of SNHG16 suppressed it. Mechanistically, miR-485-5p is a target of SNHG16, and miR-485-5p can reverse the function of SNHG16. BMP7 is also identified as a target of miR-485-5p and can be indirectly modulated by SNHG16 in hBMSCs. CONCLUSIONS: SNHG16 promotes the osteogenic differentiation of hBMSCs via regulating the miR-485-5p/BMP7 axis and comprises a prospective therapy target for OP.