Exploring distinct properties of endometrial stem cells through advanced single-cell analysis platforms.

The endometrium is a dynamic tissue that undergoes cyclic changes in response to ovarian hormones during the menstrual cycle. These changes are crucial for pregnancy establishment and maintenance. Endometrial stem cells play a pivotal role in endometrial regeneration and repair by differentiating into various cell types within the endometrium. However, their involvement in endometrial disorders such as endometriosis, infertility, and endometrial cancer is still not fully understood yet. Traditional bulk sequencing methods have limitations in capturing heterogeneity and complexity of endometrial stem cell populations. To overcome these limitations, recent single-cell analysis techniques, including single-cell RNA sequencing (scRNA-Seq), single-cell ATAC sequencing (scATAC-Seq), and spatial transcriptomics, have emerged as valuable tools for studying endometrial stem cells. In this review, although there are still many technical limitations that require improvement, we will summarize the current state-of-the-art single-cell analysis techniques for endometrial stem cells and explore their relevance to related diseases. We will discuss studies utilizing various single-cell analysis platforms to identify and characterize distinct endometrial stem cell populations and investigate their dynamic changes in gene expression and epigenetic patterns during menstrual cycle and differentiation processes. These techniques enable the identification of rare cell populations, capture heterogeneity of cell populations within the endometrium, and provide potential targets for more effective therapies.

Unveiling the potential effects of acetylsalicylic acid: insights into regeneration in endometrial stem cells.

BACKGROUND: Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity. METHODS: We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days. RESULTS: In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue. CONCLUSIONS: We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract.

Current Status and Future Outlook of Additive Manufacturing Technologies for the Reconstruction of the Trachea.

Tracheal stenosis and defects occur congenitally and in patients who have undergone tracheal intubation and tracheostomy due to long-term intensive care. Such issues may also be observed during tracheal removal during malignant head and neck tumor resection. However, to date, no treatment method has been identified that can simultaneously restore the appearance of the tracheal skeleton while maintaining respiratory function in patients with tracheal defects. Therefore, there is an urgent need to develop a method that can maintain tracheal function while simultaneously reconstructing the skeletal structure of the trachea. Under such circumstances, the advent of additive manufacturing technology that can create customized structures using patient medical image data provides new possibilities for tracheal reconstruction surgery. In this study, the three-dimensional (3D) printing and bioprinting technologies used in tracheal reconstruction are summarized, and various research results related to the reconstruction of mucous membranes, cartilage, blood vessels, and muscle tissue, which are tissues required for tracheal reconstruction, are classified. The prospects for 3D-printed tracheas in clinical studies are also described. This review serves as a guide for the development of artificial tracheas and clinical trials using 3D printing and bioprinting.

Effects of smoking on the tissue regeneration-associated functions of human endometrial stem cells via a novel target gene SERPINB2.

BACKGROUND: Smokers directly inhale mainstream cigarette smoke, which contains numerous known and potential toxic substances, and thus, smoking is expected to have broad harmful effects that cause tissue injury and dysfunction. Interestingly, many studies have suggested that the recent decline in female fertility and increased rate of spontaneous abortion could be associated with increased smoking rates. Indeed, women that smoked for 10 years or more were reported to have a ~ 20% higher infertility rate than women that had never smoked. However, the reasons for the underlying harmful aspects of smoking on female fertility remain a matter of debate. Importantly, a previous study revealed that resident endometrial stem cell deficiency significantly limits the cyclic regeneration potential of endometrium, which, in turn, decreases successful pregnancy outcomes. In this context, we postulated that exposure to mainstream cigarette smoke extracts might decrease female fertility by inhibiting the functions of resident endometrial stem cells. METHODS: We investigated whether cigarette mainstream smoke exposure directly inhibits various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, pluripotency, and differentiation capacity in vitro. Next, we determined whether SERPINB2 mediates cigarette smoke-induced suppressive effects on various tissue regeneration-associated functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. Mice were injected intraperitoneally with low (0.5 mg/kg) or high (1 mg/kg) doses of cigarette smoke extract (10 times for two weeks), and endometrial stem cells were then isolated from mice uterine tissues. RESULTS: We found that exposure to cigarette smoke extracts remarkably suppressed various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, multilineage differentiation ability, and pluripotency in vitro and in vivo by activating the SERPINB2 gene. Indeed, cigarette smoke-induced inhibitory effects on various endometrial stem cell functions were significantly abolished by SERPINB2 knockdown. CONCLUSIONS: These findings provide valuable information on the harmful effects of cigarette smoking on resident endometrial stem cells and hopefully will facilitate the developments of promising therapeutic strategies for subfertile or infertile women that smoke cigarettes.

Targeting Cancer Stem Cell Markers or Pathways: A Potential Therapeutic Strategy for Oral Cancer Treatment.

Cancer stem cells (CSCs) are a small subset of cancer cells with stem cell-like properties, self-renewal potential, and differentiation capacity into multiple cell types. Critical genetic alterations or aberrantly activated signaling pathways associated with drug resistance and recurrence have been observed in multiple types of CSCs. In this context, CSCs are considered to be responsible for tumor initiation, growth, progression, therapeutic resistance, and metastasis. Therefore, to effectively eradicate CSCs, tremendous efforts have been devoted to identify specific target molecules that play a critical role in regulating their distinct functions and to develop novel therapeutics, such as proteins, monoclonal antibodies, selective small molecule inhibitors, and small antisense RNA (asRNA) drugs. Similar to other CSC types, oral CSCs can be characterized by certain pluripotency-associated markers, and oral CSCs can also survive and form 3D tumor spheres in suspension culture conditions. These oral CSC-targeting therapeutics selectively suppress specific surface markers or key signaling components and subsequently inhibit the stem-like properties of oral CSCs. A large number of new therapeutic candidates have been tested, and some products are currently in the pre-clinical or clinical development phase. In the present study, we review new oral CSC-targeted therapeutic strategies and discuss the various specific CSC surface markers and key signaling components involved in the stem-like properties, growth, drug resistance, and tumorigenicity of oral CSCs.

3D stem cell-laden artificial endometrium: successful endometrial regeneration and pregnancy.

Thin endometrium lining or severe endometrial injury which may occur during artificial abortion can cause defective endometrial receptivity and subsequent infertility. Therefore, much effort has been devoted toward regenerating thin or damaged endometrial lining by applying multiple types of stem cells. Even though there are some positive preliminary outcomes, repairing the injured endometrium with stem cells is considerably challenging, due to the lack of an adequate microenvironment for the administrated stem cells within the tissues and subsequent poor therapeutic efficiency. In this context, as an alternative, we fabricated a 3D stem cell-laden artificial endometrium by incorporating several biodegradable biomaterials (collagen and hyaluronic acid) and multiple cellular components of endometrium (endometrial stem cells, stromal cells, and vessel cells) to properly recapitulate the multicellular microenvironment and multilayered structure. Agarose was used as an inert filler substrate to enhance the mechanical integrity of the three-layered artificial endometrium. Various mechanical characteristics, such as morphology, compression properties, swelling, and viscosity, have been evaluated. Various biological features, such as steroid hormone responsiveness, specific endometrial cell-surface marker expressions, and the secretion of multiple growth factors and steroid hormones, as well as the viability of encapsulated endometrial cells are relatively well maintained within the artificial endometrium. More importantly, severe tissue injuries were significantly relieved by transplanting our 3D artificial endometrium into endometrial ablation mice. Remarkably, artificial endometrium transplantation resulted in a successful pregnancy with subsequent live birth without any morphological or chromosomal abnormalities.

Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells.

Chronic stress has a negative impact on many fertility-related functions; thus, the recent decline in female fertility seems to be at least partially associated with increased stress. The secretion of glucocorticoids is a typical endocrine response to chronic stress and indirectly reduces uterine receptivity through the hypothalamus-pituitary-gonadal (HPG) axis. However, in addition to its well-known canonical role, the direct effects of chronic stress-induced glucocorticoids on various uterine functions and their underlying molecular mechanisms are complex and have not yet been revealed. Recent studies have found that resident stem cell deficiency is responsible for the limited regenerative potential of the endometrium (the innermost lining of the uterine cavity) during each menstrual cycle, which subsequently increases infertility rates. In this context, we hypothesized that stress-induced glucocorticoids directly damage endometrial stem cells and consequently negatively affect endometrial reconstruction, which is important for uterine receptivity. In addition to its well-known canonical roles, we identified for the first time that cortisol, the most abundant and potent glucocorticoid in humans, directly suppresses the multiple beneficial functions (self-renewal, transdifferentiation, and migratory potential) of human endometrial stem cells through its functional receptor, glucocorticoid receptor (GR). Glucocorticoids inhibit well-known survival signals, such as the PI3K/Akt and FAK/ERK1/2 pathways. More importantly, we also found that immobilization of stress-induced glucocorticoids suppresses the various beneficial functions of tissue resident stem cells in vivo. To the best of our knowledge, this is the first study to investigate the direct effects of glucocorticoids on the regenerative capacity of endometrial stem cells, and the findings will facilitate the development of more promising therapeutic approaches to increase female fertility.

Influence of Variation in Sagittal Placement of the Femoral Component after Cruciate-Retaining Total Knee Arthroplasty.

Prosthetic alignment is an important factor for long-term survival in cruciate-retaining (CR) total knee arthroplasty (TKA). The purpose of this study is to investigate the influence of sagittal placement of the femoral component on tibiofemoral (TF) kinematics and kinetics in CR-TKA. Five sagittal placements of femoral component models with -3, 0, 3, 5, and 7 degrees of flexion are developed. The TF joint kinematics, quadriceps force, patellofemoral contact force, and posterior cruciate ligament force are evaluated using the models under deep knee-bend loading. The kinematics of posterior TF translation is found to occur with the increase in femoral-component flexion. The quadriceps force and patellofemoral contact force decrease with the femoral-component flexion increase. In addition, extension of the femoral component increases with the increase in posterior cruciate ligament force. The flexed femoral component in CR-TKA provides a positive biomechanical effect compared with a neutral position. Slight flexion could be an effective alternative technique to enable positive biomechanical effects with TKA prostheses.

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer.

The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/ß-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.

Prediction of wear performance in femoral and tibial conformity in patient-specific cruciate-retaining total knee arthroplasty.

BACKGROUND: Articular surface curvature design is important in tibiofemoral kinematics and the contact mechanics of total knee arthroplasty (TKA). Thus far, the effects of articular surface curvature have not been adequately discussed with respect to conforming, nonconforming, and medial pivot designs in patient-specific TKA. Therefore, this study evaluates the underlying relationship between the articular surface curvature geometry and the wear performance in patient-specific TKA. METHODS: We compare the wear performances between conventional and patient-specific TKA under gait loading conditions using a computational simulation. Patient-specific TKAs investigated in the study are categorized into patient-specific TKA with conforming articular surfaces, medial pivot patient-specific TKA, and bio-mimetic patient-specific TKA with a patient's own tibial and femoral anatomy. The geometries of the femoral components in patient-specific TKAs are identical. RESULTS: The anterior-posterior and internal-external kinematics change with respect to different TKA designs. Moreover, the contact pressure and area did not directly affect the wear performance. In particular, conforming patient-specific TKAs exhibit the highest volumetric wear and wear rate. The volumetric wear in a conforming patient-specific TKA is 29% greater than that in a medial pivot patient-specific TKA. CONCLUSION: The findings in this study highlight that conformity changes in the femoral and tibial inserts influence the wear performance in patient-specific TKA. Kinematics and contact parameters should be considered to improve wear performance in patient-specific TKA. The conformity modification in the tibiofemoral joint changes the kinematics and contact parameters, and this affects wear performance.

A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid.

Cancer stem cells (CSCs) have been identified in a multiple of cancer types and resistant to traditional cancer therapies such as chemotherapeutic agents and radiotherapy, which may destroy bulk tumor cells but not all CSCs, contributing to reformation tumor masses and subsequent relapse. Moreover, it is very difficult to effectively identify and eliminate CSCs because they share some common phenotypic and functional characteristics of normal stem cells. Therefore, finding better therapeutic strategies to selectively target CSCs might be helpful to reduce subsequent malignancies. In the present study, we found that caffeic acid effectively suppresses self-renewal capacity, stem-like characteristics, and migratory capacity of CD44+ and CD133+ colorectal CSCs in vitro and in vivo. In addition, we also revealed that PI3K/Akt signaling may be linked to multiple colorectal CSC-associated characteristics, such as radio-resistance, stem-like property, and tumorigenic potential. To the best of our knowledge, this is the first study demonstrating that caffeic acid effectively targets colorectal CSC populations by inhibiting the growth and/or self-renewal capacity of colorectal CSCs through PI3K/Akt signaling in vitro and in vivo.

Gender differences exist in rotational anatomy of the distal femur in osteoarthritic knees using MRI.

PURPOSE: Optimal rotational alignment of the femoral component is essential for total knee arthroplasty (TKA). The femoral transepicondylar axis (TEA), Whiteside's line (WSL), and posterior condylar axis (PCA) are various intra-operative references that can be used to determine femoral rotation, and each has advantages and disadvantages. This study aimed to define the rotational anatomy of the distal femur and investigate its relationship with gender in osteoarthritic knees. METHODS: Magnetic resonance imaging (MRI) was obtained from 1522 patients (1298 females and 224 males) with end-stage knee osteoarthritis prior to TKA. MRI was constructed into three-dimensional models. The angles between the TEA and WSL, WSL and PCA, and TEA and PCA were calculated for each patient. In addition, gender differences in femoral rotation were evaluated. RESULTS: The PCA was 2.2° ± 1.0° internally rotated relative to the TEA. WSL was 1.2° ± 2.8° externally rotated relative to the TEA. The WSL to TEA relationship exhibited greater variability than the PCA to TEA relationship. PCA was more internally rotated and WSL was more externally rotated relative to TEA in female group than male group. Based on the standard reference rules of 3° external rotation from the PCA that has been conventionally used, 15.7% of patients showed external rotation lower 1° or greater than 5° external rotation from the PCA. In the mean external rotation of the TEA from the PCA (2.2°) from this population; however, the percentage of patients showing ± 2° from their TEA dropped to 5.1% of patients. CONCLUSION: Gender difference and variability exist in distal femoral rotational anatomy. These data can be useful in consideration of femoral anatomy variability and gender difference. The same cutting angle may lead to malrotation of the femoral component. LEVEL OF EVIDENCE: Consecutive patients, level III.

Morphologic difference and size mismatch in the medial and lateral tibial condyles exist with respect to gender for unicompartmental knee arthroplasty in the Korean population.

PURPOSE: The purpose of this study was to characterize the geometry of the proximal tibia in both genders in the Korean population. Anthropometric data on the medial and lateral tibial condyles of the osteoarthritic knees of 149 males and 814 females were obtained using three-dimensional magnetic resonance imaging. METHODS: In the medial and lateral proximal tibial condyles, the anteroposterior (AP) dimension, widest dimension (WD) at defined points, and condylar aspect ratio were evaluated. These measurements were compared with similar dimensions of the tibial components from five commonly used unicompartmental knee arthroplasty (UKA) designs in Korea. RESULTS: Both the AP dimension and WD in the medial and lateral tibial condyles of the male patients were significantly greater than those of the female patients (P < 0.05). In addition, the AP dimension and WD were greater in the medial than in the lateral tibial condyle (P < 0.05). There was WD overhang in three and two prostheses in the medial and lateral tibial condyles, respectively. A decrease in the condylar aspect ratio with an increasing AP dimension was found in the medial and lateral tibial condyles for both the male and female patients. CONCLUSIONS: Smaller medial and lateral tibial condylar dimensions are more frequent in Korean women than in Korean men. This study highlights the finding that conventional UKA designs lead to size mismatch in the Korean population and may indicate an important guideline on proper gender-specific UKA tibial prostheses with different WD/AP dimension aspect ratios. In addition, this study suggests that the shape of the medial tibial plateau is different to that of the lateral plateau, which can lead to a mediolateral overhang for medial UKA in an attempt to optimize the AP coverage. LEVEL OF EVIDENCE: III.

Anatomy-mimetic design preserves natural kinematics of knee joint in patient-specific mobile-bearing unicompartmental knee arthroplasty.

PURPOSE: This study aims to evaluate whether different tibial-femoral conformities for patient-specific mobile-bearing unicompartmental knee arthroplasties (UKAs) preserve natural knee kinematics, using computational simulations. METHODS: Different designs for patient-specific mobile-bearing UKAs were evaluated using finite element analysis. Three designs for the identical femoral component were considered: flat (non-conforming design), anatomy-mimetic, and conforming for the tibial insert. RESULTS: The conforming design for the patient-specific mobile-bearing UKAs exhibited a 1.2 mm and 0.7° decrease in the translation and rotation, respectively, in the swing phase compared with those of the natural knee. In addition, the femoral rollback and internal rotation were 2.6 mm and 1.2° lower, respectively, than those of the natural knee, for the conforming design under the deep-knee-bend condition. The flat design for the patient-specific mobile-bearing UKAs exhibited a 2.2 mm and 1.4° increase in the femoral rollback and rotation compared with the natural knee under the deep-knee-bend condition. The anatomy-mimetic patient-specific mobile-bearing UKAs best preserved the natural knee kinematics under the gait and deep-knee-bend loading conditions. CONCLUSIONS: The kinematics of the loading conditions in patient-specific mobile-bearing UKAs was determined to closely resemble those of a native knee. In additional, by replacing the anatomy-mimetic design with a mobile-bearing, natural knee kinematics during gait and deep-knee-bend motions is preserved. These results confirm the importance of tibiofemoral conformity in preserving native knee kinematics in patient-specific mobile-bearing UKA.

Sonic Hedgehog, a Novel Endogenous Damage Signal, Activates Multiple Beneficial Functions of Human Endometrial Stem Cells.

Local endometrial stem cells play an important role in regulating endometrial thickness, which is an essential factor for successful embryo implantation and pregnancy outcomes. Importantly, defects in endometrial stem cell function can be responsible for thin endometrium and subsequent recurrent pregnancy losses. Therefore, many researchers have directed their efforts toward finding a novel stimulatory factor that can enhance the regenerative capacity of endometrial stem cells. Sonic hedgehog (SHH) is a morphogen that plays a key role in regulating pattern formation throughout embryonic limb development. In addition to this canonical function, we identified for the first time that SHH is actively secreted as a stem cell-activating factor in response to tissue injury and subsequently stimulates tissue regeneration by promoting various beneficial functions of endometrial stem cells. Our results also showed that SHH exerts stimulatory effects on endometrial stem cells via the FAK/ERK1/2 and/or phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. More importantly, we also observed that endometrial stem cells stimulated with SHH showed markedly enhanced differentiation and migratory capacities and subsequent in vivo therapeutic effects in an endometrial ablation animal model.

Effect of sagittal femoral component alignment on biomechanics after mobile-bearing total knee arthroplasty.

BACKGROUND: Recently, there has been increasing interest in mobile-bearing total knee arthroplasty (TKA). However, changes in biomechanics with respect to femoral component alignment in mobile-bearing TKA have not been explored in depth. This study aims to evaluate the biomechanical effect of sagittal alignment of the femoral component in mobile-bearing TKA. METHODS: We developed femoral sagittal alignment models with - 3°, 0°, 3°, 5°, and 7°. We also examined the kinematics of the tibiofemoral (TF) joint, contact point on the TF joint, contact stress on the patellofemoral (PF) joint, collateral ligament force, and quadriceps force using a validated computational model under a deep-knee-bend condition. RESULTS: Posterior kinematics of the TF joint increased as the femoral component flexed. In addition, contact stress on the PF joint, collateral ligament force, and quadriceps force decreased as the femoral component flexed. The results of this study can assist surgeons in assessing risk factors associated with femoral component sagittal alignment for mobile-bearing TKA. CONCLUSIONS: Our results showed that slight flexion implantation may be an effective alternative technique because of its advantageous biomechanical effect. However, excessive flexion should be avoided because of potential loosening of the TF joint.

Design optimization of high tibial osteotomy plates using finite element analysis for improved biomechanical effect.

BACKGROUND: High tibial osteotomy (HTO) is a common treatment for moderate osteoarthritis of the medial compartment in the knee joint by the translation of the force center toward the lateral compartment. However, the stability of a short plate such as Puddu used in this procedure was not as effective as other long plates such as Tomofix. No previous studies have used a rigorous and systematic design optimization method to determine the optimal shape of short HTO plate. Therefore, the purpose of this study is to evaluate the improved biomechanical stability of a short HTO plate by using design optimization and finite element (FE) analysis. METHODS: A FE model of HTO was subjected to physiological and surgical loads in the tibia. Taguchi-style L27 orthogonal arrays were used to identify the most significant factors for optimizing the design parameters. The optimal design variables were calculated using the nondominated sorting genetic algorithm II. Plate and bone stresses and wedge micromotions in the initial and optimized designs were chosen as the comparison indices. RESULTS: Optimal designed HTO plate showed the decreased micromotions over the initial HTO plate with enhanced plate stability. In addition, increased bone stress and decreased plate stress supported the positive effect on stress shielding compared to initial HTO plate design. The results yielded a new short HTO design while demonstrating the feasibility of design optimization and potential improvements to biomechanical stability in HTO design. The newly developed short HTO plate throughout the optimization and computational simulation showed the improved biomechanical effect as good as the golden standard, TomoFix, does. CONCLUSIONS: This study showed that plate design has a strong influence on the stability after HTO. This study demonstrated that the optimized short plates had low stress shielding effect and less micromotion because of its improvement in biomechanical performances. Our result showed that design optimization is an effective tool for HTO plate design. This information can aid future developments in HTO plate design and can be expanded to other implant designs.

An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2.

Endometrial stem cells are located in the basal layer of the endometrium, and they are responsible for the cyclic regeneration of the uterus during the menstrual cycle. Recent studies have revealed that recurrent pregnancy loss is associated with an age-related stem cell deficiency in the endometrium. Therefore, intensive study of endometrial stem cell aging may provide new insights for preventing recurrent pregnancy loss. Sonic hedgehog (SHH) signaling has been identified as a morphogen during the embryonic development processes. In addition to this canonical function, we found that the age-associated decline in regenerative potential in the endometrium may be due to decreased SHH-signaling integrity in local stem cells with aging. Importantly, the current study also showed that SHH activity clearly declines with aging both in vitro and in vivo, and exogenous SHH treatment significantly alleviates various aging-associated declines in multiple endometrial stem cell functions, suggesting that SHH may act as an endogenous anti-aging factor in human endometrial stem cells. Moreover, we found that stem cell senescence may enhance SERPINB2 expression, which in turn mediates the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions, suggesting that SERPINB2 is a master regulator of SHH signaling during the aging process.

A Novel Endogenous Damage Signal, CSF-2, Activates Multiple Beneficial Functions of Adipose Tissue-Derived Mesenchymal Stem Cells.

The major challenges of current mesenchymal stem cell (MSC)-based therapeutics are their low differentiation potential into specialized cell types and their homing ability to sites of injury. Therefore, many researchers have directed their efforts toward finding a novel stimulatory factor that can significantly enhance the therapeutic effects of MSCs. Colony-stimulating factor 2 (CSF-2) is previously known as a hematopoietic growth factor involved in the differentiation of various myeloid cells from hematopoietic progenitor cells. In addition to this canonical hematopoietic function, we identified for the first time that CSF-2 is actively secreted by stem cells, in response to various types of injuries, as an endogenous damage signal that promotes the therapeutic effects of MSCs by enhancing their multi-lineage differentiation and migratory capacities, possibly through its receptor CD116. Our results also revealed that CSF-2 exerts its stimulatory effects on MSCs via PI3K/Akt- and/or FAK/ERK1/2-signaling pathways. More importantly, we also found that MSCs stimulated with CSF-2 show markedly enhanced differentiation and migratory capacities and subsequent in vivo therapeutic effects in an endometrial ablation animal model. Collectively, our findings provide compelling evidence for a novel non-hematopoietic function of CSF-2 in promoting multiple beneficial functions of MSCs via a non-canonical mechanism as an endogenous damage signal.