Effects of porcine acellular dermal matrix treatment on wound healing and scar formation: Role of Jag1 expression in epidermal stem cells.

Skin wound healing involves Notch/Jagged1 signaling. However, little is known how Jag1 expression level in epidermal stem cells (ESCs) contributes to wound healing and scar formation. We applied multiple cellular and molecular techniques to examine how Jag1 expression in ESCs modulates ESCs differentiation to myofibroblasts (MFB) in vitro, interpret how Jag1 expression in ESCs is involved in wound healing and scar formation in mice, and evaluate the effects of porcine acellular dermal matrix (ADM) treatment on wound healing and scar formation. We found that Jag1, Notch1 and Hes1 expression was up-regulated in the wound tissue during the period of wound healing. Furthermore, Jag1 expression level in the ESCs was positively associated with the level of differentiation to MFB. ESC-specific knockout of Jag1 delayed wound healing and promoted scar formation in vivo. In addition, we reported that porcine ADM treatment after skin incision could accelerate wound closure and reduce scar formation in vivo. This effect was associated with decreased expression of MFB markers, including α-SMA Col-1 and Col-III in wound tissues. Finally, we confirmed that porcine ADM treatment could increase Jag1, Notch1 and Hesl expression in wound tissues. Taken together, our results suggested that ESC-specific Jag1 expression levels are critical for wound healing and scar formation, and porcine ADM treatment would be beneficial in promoting wound healing and preventing scar formation by enhancing Notch/Jagged1 signaling pathway in ESCs.

EGFL7-overexpressing epidermal stem cells promotes fibroblast proliferation and migration via mediating cell adhesion and strengthening cytoskeleton.

Epidermal growth factor (EGF)-like family members mediate a wide range of biological activities including cell proliferation and migration. Increasing evidence indicated that EGF plays an important role in the process of wound healing by stimulating fibroblast motility. The aim of this study was to see whether EGF-like domain 7 (EGFL7)-overexpressing epidermal stem cells (EGFL7-ESCs) would promote fibroblast proliferation and migration. We found that mRNA and protein levels of EGFL7 expression were significantly increased in EGFL7-ESCs. The protein expression of EGFL7 was significantly elevated in conditioned media (CM) of EGFL7-ESCs compared to ESCs CM or vector-ESCs CM. The cell count and cell viability of EGFL7-ESCs CM-treated fibroblasts were also significantly increased compared to control. In addition, EGFL7-ESCs CM-treated fibroblasts showed elevated migration compared with control. Moreover, the expressions of ß1-integrin, ß-tubulin, ß-actin, and Vimentin were increased, while that of E-cadherin was decreased in EGFL7-ESCs CM-treated fibroblasts. These results indicate that EGFL7-ESCs contribute towards promoting fibroblast migration through enhancing cell adhesion, strengthening cytoskeleton, and reducing intercellular aggregation. These findings suggest that the stimulating effect of EGFL7-ESCs on fibroblast proliferation and migration may provide a useful strategy for wound healing.

Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway.

Chronic, non-healing wounds are a major complication of diabetes. Recently, various cell therapies have been reported for promotion of diabetic wound healing. Epidermal stem cells (ESCs) are considered a powerful tool for tissue therapy. However, the effect and the mechanism of the therapeutic properties of ESCs in the diabetic wound healing are unclear. Herein, to determine the ability of ESCs to diabetic wound healing, a dorsal skin defect in a streptozotocin (STZ)-induced diabetes mellitus (DM) mouse model was used. ESCs were isolated from mouse skin. We found that both the mRNA and protein levels of a Notch ligand Jagged1 (Jag1), Notch1 and Notch target gene Hairy Enhancer of Split-1 (Hes1) were significantly increased at the wound margins. In addition, we observed that Jag1 was high expressed in ESCs. Overexpression of Jag1 promotes ESCs migration, whereas knockdown Jag1 resulted in a significant reduction in ESCs migration in vitro Importantly, Jag1 overexpression improves diabetic wound healing in vivo These results provide evidence that ESCs accelerate diabetic wound healing via the Notch signalling pathway, and provide a promising potential for activation of the Notch pathway for the treatment of diabetic wound.

[Rosuvastatin improves myocardial function and arteriosclerosis plaque in patients with ST-segment elevation after acute myocardial infarction and percutaneous coronary intervention].

OBJECTIVE: To evaluate the effect of rosuvastatin on the functions of the surviving myocardium and arteriosclerosis plaque in patients with ST-segment elevation after acute myocardial infarction (STEMI) and percutaneous coronary intervention (PCI). METHODS: Sixty-five STEMI patients were randomized to receive 40 mg simvastatin (n=32) or 10 mg rosuvastatin (n=33) before sleep in addition to conventional medications. Before PCI and after the 12-month medications, the plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were measured, and echocardiography and (99)Tc(m)-MIBI single-photon emission computed tomography (SPECT) were performed to assess the therapeutic effects. RESULTS: At the end of 12 months, the patients in simvastatin group showed significantly reduced total cholesterol, LDL-C, CRP, TNF-α, and (99)Tc(m)-MIBI uptake fraction. In rosuvastatin group, these reductions were even more obvious; the intima media thickness (IMT) of the common carotid artery was reduced significantly after a 12-month rosuvastatin therapy, but almost remained unchanged after simvastatin therapy. CONCLUSION: Rosuvastatin therapy in addition to conventional medications can significantly reduce IMT and improve the functions of the surviving myocardium in patients with STEMI after PCI.

[B-type natriuretic peptides and subclinical target organ damage in essential hypertensive patients].

OBJECTIVE: To investigate the relationship between B-type natriuretic peptides (BNP) and subclinical target organ damage in essential hypertensive (EH) patients. METHODS: A total of 317 EH patients were divided into 3 groups according to BNP levels, namely normal (BNP<600 ng/L) group (n=102), moderate (600-883.5 ng/L) group (n=116), and elevated BNP (>883.5 ng/L) group (n=99). The blood pressure, left ventricular mass index (LVMI), the intima media thickness (IMT) of the common carotid artery, the plaque size in the coronary artery (CS) and microalbuminuria levels were analyzed in these patients. RESULTS: The EH patients with moderate and elevated BNP showed significantly higher LVMI, IMT, CS and microalbuminuria levels than those with normal BNP level (LVMI: 102.8∓23.12 and 123.9∓26.47 vs 91.09∓18.71 g/m2; IMT: 0.95∓0.32 and 1.16∓0.37 vs 0.84∓0.28 mm; microalbuminuria: 31.36∓20.55 and 36.73∓22.07 vs 23.21∓18.68, P<0.01). After adjustment, BNP was positively correlated to LVMI, IMT, CS and microalbuminuria level (r=0.45, 0.43, 0.39 and 0.41, respectively, P<0.01). Multivariate logistic regression analysis showed that age, systolic blood pressure, BNP, FPG, and microalbuminuria, LDL-C, and BMI were all related to the occurrence of subclinical target organ damages. CONCLUSION: BNP is positively correlated to subclinical target organs damages in EH patients.

[Response to metoprolol succinate sustained-release tablets in correlation to pulse pressure, serum vascular endothelial growth factor and C-reactive protein in elderly hypertensive patients with chronic heart failure].

OBJECTIVE: To investigate the effect of metoprolol succinate sustained-release tablets on cardiac function, serum vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) in elderly hypertensive patients and its relation with pulse pressure (PP). METHODS: A total of 330 elderly hypertensive patients with chronic heart failure receiving basic therapy were included. Before initiation and 3 months after the maximal tolerated dose of metoprolol succinate sustained-release tablets, the parameters of blood pressure, clinical features, radionuclide ventriculographic and laboratory findings of the patients were analyzed. RESULTS: As the PP was elevated, the serum levels of VEGF, hs-CRP and BNP increased and the cardiac systolic and diastolic functions decreased. In patients with PP of 59-68 mmHg and > 68 mmHg, 3 months of treatment with the tablets caused significantly increased LVEF by (3.32 ± 2.35)% and (4.12 ± 3.05)% and LVPER by 0.37 ± 0.26 and 0.53 ± 0.37, respectively; PP were decreased by 8.2 ± 3.1 mmHg and 9.4 ± 4.3 mmHg and VEGF by 18.39 ± 8.43 pg/ml and 26.79 ± 14.32 pg/ml, respectively. The treatment also resulted in lowered hs-CRP and BNP in these patients by 0.26 ± 0.13 mg/L and 0.33 ± 0.16 mg/L and by 140.36 ± 68.62 ng/L and 155.39 ± 73.58 ng/L, respectively. CONCLUSION: Obvious elevation of PP is associated with a better response to metoprolol succinate sustained-release tablets in elderly hypertensive patients with chronic heart failure, and 3 months of treatment with the tablets can significantly improve the cardiac function and lower the levels of VEGF, hs-CRP and BNP in these patients.

[Effects of rosuvastatin on left ventricular cardiac function, arteriosclerotic plaque and high sensitive C-reactive protein in hypertensive patients with mild LDL-C elevation].

OBJECTIVE: To observe the effect of rosuvastatin on left ventricular cardiac function, arteriosclerotic plaque and high sensitive C-reactive protein (hs-CRP) in hypertensive patients with mild elevation of LDL-C. METHODS: Seventy-nine patients with a SBP of 140-179 mmHg and/or a DBP of 90-109 mmHg and mild elevated LDL-C were treated with rosuvastatin for 12 months (n=40) or not (n=39). The changes of hs-CRP, arteriosclerosis plaque and cardiac function at the end of the 12-months treatment relative to the baseline levels were analyzed. RESULTS: After 12 months of treatment, LDL-C was decreased by 33.2% in rosuvastatin group but remained unchanged in patients without rosuvastatin treatment. The left ventricular peak filling rate (LVPFR) increased significantly from 1.85 to 2.59 (P<0.05) and the serum levels of hs-CRP reduced significantly (P<0.05) after rosuvastatin treatment. The size of the plaques reduced significantly after a 12-month rosuvastatin therapy. CONCLUSION: Rosuvastatin therapy on the basis of conventional anti-hypertensive drugs can obviously improve the left ventricular diastolic function and produce favorable effects on arteriosclerotic plaques.

[Clinical application of xenogenic (porcine) acellular dermal atrix (ADM) in scar treatment].

OBJECTIVE: To investigate the role of xenogenic (porcine) ADM as dermal substitute in scar treatment. METHODS: After scar excision, the wounds were covered with composite grafts of DR procine ADM and autologous thin split-thickness grafts in one stage or in two stages. RESULTS: 22 out of 47 cases were treated in two-staged procedure. After the ADMs were applied to the wound, the autologous thin split-thickness grafts were implanted 7 days later. 25 cases were treated in one-staged procedure. The survival rates of composite grafts were (88.3 +/- 3.7)% for subcutaneous recipient bed and (89.7 +/- 3.4)% for deep fascia recipient bed in group with two-staged procedure, compared with (92.5 +/- 4.1)% and (93.2 +/- 5.2)%, respectively, in group with one-staged procedure. Early after grafts taken, the grafts had a pink colour and smooth surface. The patients were followed up for 90 days at most. The survived composite grafts were durable, elastic, smooth and soft with good function and appearance like normal skin. They could even be pinched up. The scar along the edge of the grafts was slightly hypertrophic. CONCLUSIONS: The survival rate of composite graft is higher in patients with one-staged procedure. The elasticity and textural of the taken grafts are better on subcutaneous recipient bed than on deep fascia recipient bed, though the function has no difference. Xenogenic (porcine) ADM can be an optimal dermal substitute for wound coverage after scar excision.

[Treatment of deep partial thickness burns by a single dressing of porcine acellular dermal matrix].

OBJECTIVE: To explore the effect of one dressing of porcine acellular dermal matrix on deep partial thickness burns. METHODS: From January 1997 to January 2004, sixty-seven cases of deep partial thickness total burned surface area (TBSA) from 50% to 90% burn wound were treated by a single dressing of porcine acellular dermal matrix (the porcine acellular dermal matrix group). Ten cases of deep partial thickness burned patients with the same TBSA treated by exposure method served as the exposure method group. The healing time of the wound was observed. The patients were followed up for 3 months to 2 years, and the scar proliferation was observed. RESULTS: The deep partial-thickness wound would be healed without dressing change in the porcine acellular dermal matrix group, and the average healing time was (12.2 +/- 2.6) days. The average healing time of the exposure method group was (27.4 +/- 3.5) days. Follow up of the patients within 3 months to 2 years showed that scar proliferation in the porcine acellular dermal matrix group was much less than that in the exposure method group, even no scar proliferation was observed in some patients. CONCLUSION: Without tangential excision, autografting and dressing change, a single dressing of porcine acellular dermal matrix on deep partial thickness burn wound could shorten the healing time and inhibit scar proliferation.