Predicting the probability of a live birth after a freeze-all based in vitro fertilization-embryo transfer (IVF-ET) treatment strategy.

Background: The predictors for live birth rate (LBR) following one episode of in vitro fertilization (IVF) cycle for patients using a "freeze-all" strategy are not entirely clear. Methods: A retrospective cohort study utilizing a prediction model was developed to assess the relationship to the LBR. Women undergoing IVF with a freeze-all strategy were screened. Univariate models were first fitted for female age at oocytes retrieval/frozen-thawed embryo transfer (FET), body mass index (BMI), duration and etiology of infertility, previous IVF failures, total dose and duration of gonadotrophin, ovarian sensitivity index (OSI), number of oocytes collected, method of fertilization, number of embryos created, number and stage of embryos frozen, type and number of FET cycles, endometrial thickness (EMT)/pattern, hormone level on transplantation day, storage duration, number of embryos thawed and damaged thawed embryos, number and stage of embryos transferred and number of different quality embryos transferred. Variables with P<0.05 in the univariate model were selected for further analysis of the final multivariate discrete-time logistic regression model. Results: A total of 7,602 women undergoing one ovarian stimulation resulted in 9,964 FETs, of whom 3,066 (40.33%) had a live-birth after their first FET and 3,929 (51.68%) after total FETs. The EMT and woman's age at oocyte retrieval were the most important predictors. In the first FET, the LBR of women with an EMT ≤8 mm [27.40%; 95% confidence interval (CI): (21.60-33.81%)] was significantly lower than that of women with EMT between 9 and 11 mm [36.51%; 95% CI: (34.25-38.81%)] and thicker than 12 mm [44.23%; 95% CI: (42.22-46.25%)] (P<0.05). The optimistic and conservative cumulative LBRs of women younger than 31 years [87.5%; 95% CI: (86.32-88.61%) and 63.04%; 95% CI: (61.36-64.69%)] were significantly decreased in women aged 31-35, 36-40 and >40 (P<0.001). Conclusions: Our study provides an effective prediction model for a woman's chance of having a baby after a "freeze-all" policy. The use of EMT and female age as tools to identify LBR are shown to be justified, and repeated FETs cannot reverse the age-dependent decline in fertility.

The ASIC3-M-CSF-M2 macrophage-positive feedback loop modulates fibroblast-to-myofibroblast differentiation in skin fibrosis pathogenesis.

Inflammation is one of the main pathological features leading to skin fibrosis and a key factor leading to the progression of skin fibrosis. Acidosis caused by a decrease in extracellular pH is a sign of the inflammatory process. Acid-sensing ion channels (ASICs) are ligand-gated ion channels on the cell membrane that sense the drop in extracellular pH. The molecular mechanisms by which skin fibroblasts are regulated by acid-sensing ion channel 3 (ASIC3) remain unknown. This study investigated whether ASIC3 is related to inflammation and skin fibrosis and explored the underlying mechanisms. We demonstrate that macrophage colony-stimulating factor (M-CSF) is a direct target of ASIC3, and ASIC3 activation promotes M-CSF transcriptional regulation of macrophages for M2 polarization. The polarization of M2 macrophages transduced by the ASIC3-M-CSF signal promotes the differentiation of fibroblasts into myofibroblasts through transforming growth factor ß1 (TGF-ß1), thereby producing an ASIC3-M-CSF-TGF-ß1 positive feedback loop. Targeting ASIC3 may be a new treatment strategy for skin fibrosis.

Fibroblasts: Heterogeneous Cells With Potential in Regenerative Therapy for Scarless Wound Healing.

In recent years, research on wound healing has become increasingly in-depth, but therapeutic effects are still not satisfactory. Occasionally, pathological tissue repair occurs. Influencing factors have been proposed, but finding the turning point between normal and pathological tissue repair is difficult. Therefore, we focused our attention on the most basic level of tissue repair: fibroblasts. Fibroblasts were once considered terminally differentiated cells that represent a single cell type, and their heterogeneity was not studied until recently. We believe that subpopulations of fibroblasts play different roles in tissue repair, resulting in different repair results, such as the formation of normal scars in physiological tissue repair and fibrosis or ulcers in pathological tissue repair. It is also proposed that scarless healing can be achieved by regulating fibroblast subpopulations.

Human dermal fibroblasts support the development of human primordial/primary follicles in a 3-dimensional alginate matrix culture system.

BACKGROUND: Alginate matrix 3-dimensional culture offers the opportunity for the development and maturation of human secondary follicles in vitro. However, alginate may not be the most suitable culture system for human primordial/primary follicles in vitro. Thus, the innovation of alginate matrix 3-dimensional culture systems for human primordial/primary follicles could hold promise as an ideal approach to restoring fertility. METHODS: We extracted primordial/primary follicles from ovarian tissues collected from patients with non-ovarian benign gynecological conditions. Fibroblasts were isolated from dermal tissue from 1 male patient who had undergone posthectomy. The isolated human follicles were randomly divided into 2 groups and encapsulated within fibroblast-alginate-hydrogels or alginate hydrogels. The survival and growth of human primordial/primary follicles were measured after 21 days of in vitro culture. RESULTS: The dermal fibroblasts in alginate hydrogel microcapsules were round in shape, and were distributed as uniform clouds on the surface and gaps of the alginate. After 21 days of culture, the survival rate of follicles in the fibroblast-alginate group was higher than that of the alginate group (P<0.05). The diameter of follicles in the fibroblast-alginate group and the alginate group after 21 days of culture was 152.80±13.64 and 129.14±9.95 µm, respectively (P<0.05). After 21-day culture, the mean cpm (log-converted) for 3H-thymidine incorporated by granulosa cells in the fibroblast-alginate and alginate groups was 6.87±0.24 and 4.63±0.38, respectively (P<0.05). After 21 days of culture, the messenger RNA expression levels of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) were significantly higher in oocytes in fibroblast-alginate hydrogels than in those in alginate hydrogels (P<0.05). CONCLUSIONS: Human fibroblasts are beneficial to the development of human follicles in 3-dimensional culture alginate gel systems over a long period of time. More studies are required to investigate the molecular biological mechanisms of human fibroblasts that promote follicle growth in vitro.

The Smad Dependent TGF-ß and BMP Signaling Pathway in Bone Remodeling and Therapies.

Bone remodeling is a continuous process that maintains the homeostasis of the skeletal system, and it depends on the homeostasis between bone-forming osteoblasts and bone-absorbing osteoclasts. A large number of studies have confirmed that the Smad signaling pathway is essential for the regulation of osteoblastic and osteoclastic differentiation during skeletal development, bone formation and bone homeostasis, suggesting a close relationship between Smad signaling and bone remodeling. It is known that Smads proteins are pivotal intracellular effectors for the members of the transforming growth factor-ß (TGF-ß) and bone morphogenetic proteins (BMP), acting as transcription factors. Smad mediates the signal transduction in TGF-ß and BMP signaling pathway that affects both osteoblast and osteoclast functions, and therefore plays a critical role in the regulation of bone remodeling. Increasing studies have demonstrated that a number of Smad signaling regulators have potential functions in bone remodeling. Therefore, targeting Smad dependent TGF-ß and BMP signaling pathway might be a novel and promising therapeutic strategy against osteoporosis. This article aims to review recent advances in this field, summarizing the influence of Smad on osteoblast and osteoclast function, together with Smad signaling regulators in bone remodeling. This will facilitate the understanding of Smad signaling pathway in bone biology and shed new light on the modulation and potential treatment for osteoporosis.

Insights into the role of adipose-derived stem cells: Wound healing and clinical regenerative potential.

The incidence of acute and chronic wound diseases is rising due to various reasons. With complicated pathogenesis, long course, difficult treatment and high disability, wound diseases have become a major burden for patients, their families, and society. Therefore, the focus of research is to identify new ideas and methods for treatment. Fat grafting has gained increased attention because of its effectiveness in wound treatment, and further analysis has uncovered that the stem cells derived from fat may be the main factor affecting wound healing. We summarize the function of adipose stem cells and analyze their possible mechanisms in tissue repair, helping to provide new ideas for the treatment of wound healing.

Emerging Role of IL-10 in Hypertrophic Scars.

Hypertrophic scars (HS) arise from traumatic or surgical injuries and the subsequent abnormal wound healing, which is characterized by continuous and histologically localized inflammation. Therefore, inhibiting local inflammation is an effective method of treating HS. Recent insight into the role of interleukin-10 (IL-10), an important anti-inflammatory cytokine, in fibrosis has increased our understanding of the pathophysiology of HS and has suggested new therapeutic targets. This review summarizes the recent progress in elucidating the role of IL-10 in the formation of HS and its therapeutic potential based on current research. This knowledge will enhance our understanding of the role of IL-10 in scar formation and shed new light on the regulation and potential treatment of HS.

[Primarily application of Ilizarov microcirculation reconstruction technique for chronic wounds in post-traumatic ischemia limbs].

OBJECTIVE: To evaluate the treatment results of Ilizarov microcirculation reconstruction technique for chronic wounds in the post-traumatic ischemia limbs. METHODS: Between January 2016 and July 2019, 7 cases of chronic wounds in the post-traumatic ischemia limbs were treated. There were 5 males and 2 females, with an average age of 42.4 years (range, 29-66 years). The duration of the wound ranged from 1 month to 2 years (mean, 7.7 months). The wounds located in the leg (3 cases) or in the foot and ankle (4 cases). The wound sizes ranged from 4.0 cm×2.2 cm to 12.0 cm×7.1 cm. There were 1 case of tibial varus, 3 cases of equinovarus, 1 case of scleroderma, and 2 cases of Volkmann's ischemic contracture. After debridement, external fixators were used for tibial transverse transport, or correction of tibial varus and correction of equinovarus. RESULTS: All patients were followed up 8-20 months, with an average of 13 months. The infection of wound surface was all controlled in 7 cases and the granulation tissue grew well; the wound surface healed directly in 5 cases and healed after skin grafting in 2 cases, and the wound healing time was 1-3 months (mean, 1.7 months). During the follow-up, there was no recurrence of the wound. Six cases of limb deformity were corrected. CONCLUSION: For the chronic wounds in the post-traumatic ischemia limbs, Ilizarov microcirculation reconstruction technique can effectively improve local circulation and facilitate the fresh granule growth and wound healing.

Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation.

BACKGROUND: Hypertrophic scar (HS) is characterized by the increased proliferation and decreased apoptosis of myofibroblasts. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts. Thus, the stimulation of myofibroblast apoptosis is a possible treatment for HS. We aimed to explore that whether over-activated myofibroblasts can be targeted for apoptosis by anticancer drug elesclomol. METHODS: 4',6-diamidino-2-phenylindole staining, flow cytometry, western blotting, collagen gel contraction and immunofluorescence assays were applied to demonstrate the proapoptotic effect of elesclomol in scar derived myofibroblasts and TGF-ß1 induced myofibroblasts. The therapeutic potential of elesclomol was investigated by establishing rabbit ear hypertrophic scar models. FINDINGS: Both 4',6-diamidino-2-phenylindole staining and flow cytometry indicated that elesclomol targets myofibroblasts in vitro. Collagen gel contraction assay showed that elesclomol inhibited myofibroblast contractility. Flow cytometry and western blot analysis revealed that elesclomol resulted in excessive intracellular levels of reactive oxygen species(ROS), and caspase-3 and cytochrome c proteins. Moreover, compared with the control group, the elesclomol group had a significantly lower scar elevation index in vivo. Immunofluorescence assays for TUNEL and α-smooth muscle actin indicated that elesclomol treatment increased the number of apoptotic myofibroblasts. INTERPRETATION: The above results indicate that elesclomol exerted a significant inhibitory effect on HS formation via targeted myofibroblast apoptosis associated with increased oxidative stress. Thus, elesclomol is a promising candidate drug for the treatment of myofibroblast-related diseases such as HS.

m6 A facilitates YTHDF-independent phase separation.

N6-methyladenosine (m6 A) is one of the most abundant messenger RNA (mRNA) modifications in eukaryotes and is involved in various key processes of RNA metabolism. In this issue of Nature, Ries et al (2019) described the fundamental features of m6A modification of mRNAs in regulating the composition of the phase-separated transcriptome on the basis of number and distribution, and provide strong evidence that m6A plays a role in regulating phase separation in cells.

Direct and Indirect Roles of Macrophages in Hypertrophic Scar Formation.

Hypertrophic scars are pathological scars that result from abnormal responses to trauma, and could cause serious functional and cosmetic disability. To date, no optimal treatment method has been established. A variety of cell types are involved in hypertrophic scar formation after wound healing, but the underlying molecular mechanisms and cellular origins of hypertrophic scars are not fully understood. Macrophages are major effector cells in the immune response after tissue injury that orchestrates the process of wound healing. Depending on the local microenvironment, macrophages undergo marked phenotypic and functional changes at different stages during scar pathogenesis. This review intends to summarize the direct and indirect roles of macrophages during hypertrophic scar formation. The in vivo depletion of macrophages or blocking their signaling reduces scar formation in experimental models, thereby establishing macrophages as positive regulatory cells in the skin scar formation. In the future, a significant amount of attention should be given to molecular and cellular mechanisms that cause the phenotypic switch of wound macrophages, which may provide novel therapeutic targets for hypertrophic scars.

Epithelial-mesenchymal transition in the formation of hypertrophic scars and keloids.

Abnormal wound healing is likely to induce the formation of hypertrophic scars and keloids, which leads to dysfunction, deformity, and mental problem in the patients. Despite the advances in prevention and management of hypertrophic scar and keloids, the mechanism underlying scar and keloid formation has not been fully elucidated. Recent insights into the role of the epithelial-mesenchymal transition (EMT) in development, wound healing, stem cell regulation, fibrosis, and tumorigenesis have increased our understanding of the pathophysiology of hypertrophic scarring and keloids and suggested new therapeutic targets. This review summarizes recent progress in the elucidation of the role of EMT in physiologic wound healing and pathologic scar formation. This knowledge will facilitate an understanding of EMT roles in scar formation and shed new light on the modulation and potential treatment of hypertrophic scars and keloids.