Double Inferior Vena Cava with Major Predominance of the Left Inferior Vena Cava: A Cadaver Case Report.

We encountered a case of a double inferior vena cava with major predominance of the left inferior vena cava during an anatomical dissection course for medical students in 2015. The right inferior vena cava (normal inferior vena cava) was 2.0 mm wide, and the left inferior vena cava was 23.2 mm wide. The fine right inferior vena cava began at the right common iliac vein, ascended along the right side of the abdominal aorta, and then joined the left inferior vena cava at the level of the lower margin of the first lumbar vertebra. The dominant left inferior vena cava started from the left common iliac vein and ascended along the left side of the abdominal aorta. Most patients with a double inferior vena cava are asymptomatic, and these variants are incidentally detected by computed tomography or magnetic resonance imaging. Their presence may have significant implications for surgery, particularly abdominal surgery in patients with paraaortic lymphadenopathy and in those undergoing laparoscopic radical nephrectomy or inferior vena cava filter placement. We herein discuss the embryology of a double inferior vena cava based on detailed anatomical data of the variations of a double inferior vena cava, including those that require clinical attention.

The Key Structure of the Facial Soft Tissue: The Superficial Musculoaponeurotic System.

The superficial musculoaponeurotic system (SMAS) was advocated by Mitz and Peyronie in 1976. The concept of this superficial fascia was established by surgical findings of facelift surgery and is familiar to plastic surgeons and anatomists. However, detailed characteristics of this fascia are still not widely known among head and neck surgeons. Moreover, the SMAS is generally located at the parotid and cheek regions and divides facial fat into superficial and deep layers. The SMAS connects to the superficial temporal fascia cranially and to the platysma caudally. The frontal muscle and the peripheral part of the orbicularis oculi are also in the same plane. The exact expanse of the SMAS in the face is controversial. Some authors claimed that the SMAS exists in the upper lip, whereas others denied the continuity of the SMAS to the superficial temporal fascia in a histological study. There are various other opinions regarding SMAS aside from those mentioned above. The concept of the SMAS is very important for facial soft tissue surgeries because the SMAS is a good surgical landmark to avoid facial nerve injuries. Therefore, this article summarized SMAS from an anatomical point of view.

An Anatomical Dissection Method for Observation of Fibrous Facial Structures.

BACKGROUND: In recent years, structures including the superficial musculoaponeurotic system and retaining ligaments that support the facial soft tissue have been clarified. However, these structures are very difficult to observe in their entirety by the standard gross anatomical procedure (ie, dissection from superficial to deep layers). Furthermore, accurate descriptions of these structures are rare in both anatomical and plastic surgery textbooks. The aim of this study was to clarify the facial fibrous structures in a gross anatomical view. METHODS: The authors' novel method used soft facial tissue and bone. The tissue was fixed in gelatin and sectioned at a thickness of 5 to 10 mm. Each section was placed on a wooden board; the bone was then pinned, and the skin was pulled outward with sutures to hyperextend the soft tissue. Subsequently, the loose connective tissue was torn and fat tissue was removed under a surgical microscope. After the removal of fat tissue, the fibrous facial structures (eg, the superficial musculoaponeurotic system and retaining ligaments) could be observed clearly. RESULTS: The thickness of the sections allowed three-dimensional observation, such that a structure located deep within a section could be clearly observed. The expansion of soft tissue facilitated observation of the facial layer and fibrous structures, and the locations of nerves and vessels. Therefore, the facial layer structure was readily discerned. CONCLUSION: This method is likely to be very useful in the field of plastic surgery because it enabled intuitive identification of facial layers and their characteristics. CLINICAL RELEVANCE STATEMENT: The dissection method developed by the authors reveals the connected morphology of each tissue of the face, thus providing basic data for analyzing soft tissue changes due to aging and gravity. This will be useful for the development of anti-aging medicine.

Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect.

Induced pluripotent stem cells (iPSCs) are a promising resource for allogeneic cartilage transplantation to treat articular cartilage defects that do not heal spontaneously and often progress to debilitating conditions, such as osteoarthritis. However, to the best of our knowledge, allogeneic cartilage transplantation into primate models has never been assessed. Here, we show that allogeneic iPSC-derived cartilage organoids survive and integrate as well as are remodeled as articular cartilage in a primate model of chondral defects in the knee joints. Histological analysis revealed that allogeneic iPSC-derived cartilage organoids in chondral defects elicited no immune reaction and directly contributed to tissue repair for at least four months. iPSC-derived cartilage organoids integrated with the host native articular cartilage and prevented degeneration of the surrounding cartilage. Single-cell RNA-sequence analysis indicated that iPSC-derived cartilage organoids differentiated after transplantation, acquiring expression of PRG4 crucial for joint lubrication. Pathway analysis suggested the involvement of SIK3 inactivation. Our study outcomes suggest that allogeneic transplantation of iPSC-derived cartilage organoids may be clinically applicable for the treatment of patients with chondral defects of the articular cartilage; however further assessment of functional recovery long term after load bearing injuries is required.

Generation of Monkey Induced Pluripotent Stem Cell-Derived Cartilage Lacking Major Histocompatibility Complex Class I Molecules on the Cell Surface.

Due to the poor capacity for articular cartilage to regenerate, its damage tends to result in progressively degenerating conditions such as osteoarthritis. To repair the damage, the transplantation of allogeneic human induced pluripotent stem cell (iPSC)-derived cartilage is being considered. However, although allogeneic cartilage transplantation is effective, immunological reactions can occur. One hypothetical solution is to delete the expression of major histocompatibility complex (MHC) class I molecules to reduce the immunological reactions. For this purpose, we deleted the ß2 microglobulin (B2M) gene in a cynomolgus monkey (crab-eating monkey [Macaca fascicularis]) iPS cells (cyiPSCs) to obtain B2M-/- cyiPSCs using the CRISPR/Cas9 system. Western blot analysis confirmed B2M-/- cyiPSCs lacked B2M protein, which is necessary for MHC class I molecules to be transported to and expressed on the cell surface by forming multimers with B2M. Flow cytometry analysis revealed no B2M-/- cyiPSCs expressed MHC class I molecules on their surface. The transplantation of B2M-/- cyiPSCs in immunodeficient mice resulted in teratoma that contained cartilage, indicating that the lack of MHC class I molecules on the cell surface affects neither the pluripotency nor the chondrogenic differentiation capacity of cyiPSCs. By modifying the chondrogenic differentiation protocol for human iPSCs, we succeeded at differentiating B2M+/+ and B2M-/- cyiPSCs toward chondrocytes followed by cartilage formation in vitro, as indicated by histological analysis showing that B2M+/+ and B2M-/- cyiPSC-derived cartilage were positively stained with safranin O and expressed type II collagen. Flow cytometry analysis confirmed that MHC class I molecules were not expressed on the cell surface of B2M-/- chondrocytes isolated from B2M-/- cyiPSC-derived cartilage. An in vitro mixed lymphocyte reaction assay showed that neither B2M+/+ nor B2M-/- cyiPSC-derived cartilage cells stimulated the proliferation of allogeneic peripheral blood mononuclear cells. On the contrary, osteochondral defects in monkey knee joints that received allogeneic transplantations of cyiPSC-derived cartilage showed an accumulation of leukocytes with more natural killer cells around B2M-/- cyiPSC-derived cartilage than B2M+/+ cartilage, suggesting complex mechanisms in the immune reaction of allogeneic cartilage transplanted in osteochondral defects in vivo. Impact statement The transplantation of allogeneic induced pluripotent stem cell (iPSC)-derived cartilage is expected to treat articular cartilage damage, although the effects of major histocompatibility complex (MHC) in immunological reactions have not been well studied. We succeeded at creating B2M-/- cynomolgus monkey (cy)iPSCs and cyiPSC-derived cartilage that lack MHC class I molecules on the cell surface. B2M-/- cyiPSC-derived cartilage cells did not stimulate the proliferation of allogeneic peripheral blood mononuclear cells in vitro. On the contrary, the transplantation of B2M-/- cyiPSC-derived cartilage into osteochondral defects in monkey knee joints resulted in survival of transplants and accumulation of leukocytes, including natural killer cells, suggesting complex mechanisms for the immune reaction.

Revision Total Hip Arthroplasty due to Catastrophic Osteolysis Caused by Massive Chronic Expanding Hematoma.

An 84-year-old woman who underwent bilateral cementless total hip arthroplasty (THA) for dysplastic osteoarthritis 22 years ago was subjected to analysis. A huge soft-tissue mass was revealed in her left medial thigh. Plain radiographs of the left hip joint revealed severe osteolysis around the stem, cup, and ischium. Magnetic resonance imaging showed a 25 × 14-cm multilobulated mass with a thick-walled pseudocapsule. Two-stage surgery was performed with resection of the mass followed by a subsequent revision THA. The mass was diagnosed as a chronic expanding hematoma through gross and histologic findings. Two years after the revision THA, there was no recurrence of a hematoma. Two-stage revision THA was useful for definitive diagnosis, and good functional recovery was obtained after surgery.

Recent progress of animal transplantation studies for treating articular cartilage damage using pluripotent stem cells.

Focal articular cartilage damage can eventually lead to the onset of osteoarthritis with degradation around healthy articular cartilage. Currently, there are no drugs available that effectively repair articular cartilage damage. Several surgical techniques exist and are expected to prevent progression to osteoarthritis, but they do not offer a long-term clinical solution. Recently, regenerative medicine approaches using human pluripotent stem cells (PSCs) have gained attention as new cell sources for therapeutic products. To translate PSCs to clinical application, appropriate cultures that produce large amounts of chondrocytes and hyaline cartilage are needed. So too are assays for the safety and efficacy of the cellular materials in preclinical studies including animal transplantation models. To confirm safety and efficacy, transplantation into the subcutaneous space and articular cartilage defects have been performed in animal models. All but one study we reviewed that transplanted PSC-derived cellular products into articular cartilage defects found safe and effective recovery. However, for most of those studies, the quality of the PSCs was not verified, and the evaluations were done with small animals over short observation periods. Large animals and longer observation times are preferred. We will discuss the recent progress and future direction of the animal transplantation studies for the treatment of focal articular cartilage damages using PSCs.

Quality assessment tests for tumorigenicity of human iPS cell-derived cartilage.

Articular cartilage damage does not heal spontaneously and causes joint dysfunction. The implantation of induced pluripotent stem cell (iPSC)-derived cartilage (iPS-Cart) is one candidate treatment to regenerate the damaged cartilage. However, concerns of tumorigenicity are associated with iPS-Cart, because the iPSC reprogramming process and long culture time for cartilage induction could increase the chance of malignancy. We evaluated the tumorigenic risks of iPS-Cart using HeLa cells as the reference. Spike tests revealed that contamination with 100 HeLa cells in 150 mg of iPS-Cart accelerated the cell growth rate. On the other hand, 150 mg of iPS-Cart without HeLa cells reached growth arrest and senescence after culture, suggesting less than 100 tumorigenic cells, assuming they behave like HeLa cells, contaminated iPS-Cart. The implantation of 10,000 or fewer HeLa cells into joint surface defects in the knee joint of nude rat did not cause tumor formation. These in vitro and in vivo studies collectively suggest that the implantation of 15 g or less iPS-Cart in the knee joint does not risk tumor formation if assuming that the tumorigenic cells in iPS-Cart are equivalent to HeLa cells and that nude rat knee joints are comparable to human knee joints in terms of tumorigenicity. However, considering the limited immunodeficiency of nude rats, the clinical amount of iPS-Cart for implantation needs to be determined cautiously.

Changes in acetyl-CoA mediate Sik3-induced maturation of chondrocytes in endochondral bone formation.

The maturation of chondrocytes is strictly regulated for proper endochondral bone formation. Although recent studies have revealed that intracellular metabolic processes regulate the proliferation and differentiation of cells, little is known about how changes in metabolite levels regulate chondrocyte maturation. To identify the metabolites which regulate chondrocyte maturation, we performed a metabolome analysis on chondrocytes of Sik3 knockout mice, in which chondrocyte maturation is delayed. Among the metabolites, acetyl-CoA was decreased in this model. Immunohistochemical analysis of the Sik3 knockout chondrocytes indicated that the expression levels of phospho-pyruvate dehydrogenase (phospho-Pdh), an inactivated form of Pdh, which is an enzyme that converts pyruvate to acetyl-CoA, and of Pdh kinase 4 (Pdk4), which phosphorylates Pdh, were increased. Inhibition of Pdh by treatment with CPI613 delayed chondrocyte maturation in metatarsal primordial cartilage in organ culture. These results collectively suggest that decreasing the acetyl-CoA level is a cause and not result of the delayed chondrocyte maturation. Sik3 appears to increase the acetyl-CoA level by decreasing the expression level of Pdk4. Blocking ATP synthesis in the TCA cycle by treatment with rotenone also delayed chondrocyte maturation in metatarsal primordial cartilage in organ culture, suggesting the possibility that depriving acetyl-CoA as a substrate for the TCA cycle is responsible for the delayed maturation. Our finding of acetyl-CoA as a regulator of chondrocyte maturation could contribute to understanding the regulatory mechanisms controlling endochondral bone formation by metabolites.

Integration Capacity of Human Induced Pluripotent Stem Cell-Derived Cartilage.

IMPACT STATEMENT: Cartilage particles derived from human induced pluripotent stem cells (hiPS-Carts) are one candidate source for transplants for treatment of articular cartilage damage. This study shows that hiPS-Carts integrate with each other in an in vitro model and analyzed the course of the integration. The integration starts at the perichondrium-like membrane at around 1 week and then progresses to the central cartilage within 4-8 weeks. The results indicate that FGF18 secreted from the perichondrium-like membrane accelerates the initial step of integration. The findings contribute to understanding how hiPS-Carts form repair tissue and provide clue to accelerate healing after transplantation.

Considerations in hiPSC-derived cartilage for articular cartilage repair.

BACKGROUND: A lack of cell or tissue sources hampers regenerative medicine for articular cartilage damage. MAIN TEXT: We review and discuss the possible use of pluripotent stem cells as a new source for future clinical use. Human induced pluripotent stem cells (hiPSCs) have several advantages over human embryonic stem cells (hESCs). Methods for the generation of chondrocytes and cartilage from hiPSCs have been developed. To reduce the cost of this regenerative medicine, allogeneic transplantation is preferable. hiPSC-derived cartilage shows low immunogenicity like native cartilage, because the cartilage is avascular and chondrocytes are segregated by the extracellular matrix. In addition, we consider our experience with the aberrant deposition of lipofuscin or melanin on cartilage during the chondrogenic differentiation of hiPSCs. SHORT CONCLUSION: Cartilage generated from allogeneic hiPSC-derived cartilage can be used to repair articular cartilage damage.

Limited Immunogenicity of Human Induced Pluripotent Stem Cell-Derived Cartilages.

Articular cartilage damage does not spontaneously heal and could ultimately result in a loss of joint function. Damaged cartilage can be repaired with cell/tissue sources that are transplanted, however, autologous chondrocytes are limited in number as a cell source. Induced pluripotent stem cells (iPSCs) are a relatively new and abundant cell source and can be made from the patient, but at a considerable cost. Because cartilage is immunoprivileged tissue, allogeneic cartilages have been transplanted effectively without matching for human leukocyte antigen (HLA), but are difficult to acquire due to scarcity of donors. In this study, we examined the immunogenicity of human iPSC-derived cartilages (hiPS-Carts) in vitro to evaluate whether allogeneic hiPS-Carts can be a new cell/tissue source. The cells in hiPS-Carts expressed limited amounts of major histocompatibility complex (MHC) class I (HLA-ABC) and MHC class II (HLA-DRDQDP). Treatment with interferon γ (IFNγ) induced the expression of MHC class I, but not MHC class II in hiPS-Carts. A mixed lymphocyte reaction assay showed that hiPS-Carts stimulated the proliferation of neither T cells nor the activation of NK cells. Furthermore, hiPS-Carts suppressed the proliferation of T cells stimulated with interleukin 2 and phytohemagglutinin (PHA). Together with previously reported findings, these results suggest that hiPS-Carts are no more antigenic than human cartilage. Additionally, in combination with the fact that iPSCs are unlimitedly expandable and thus can supply unlimited amounts of iPS-Carts from even one iPSC line, they suggest that allogeneic hiPS-Carts are a candidate source for transplantation to treat articular cartilage damage.

Prevalence of elevated serum anti-N-methyl-D-aspartate receptor antibody titers in patients presenting exclusively with psychiatric symptoms: a comparative follow-up study.

BACKGROUND: Increasing numbers of patients with elevated anti-N-methyl-D-aspartate (NMDA) receptor antibody titers presenting exclusively with psychiatric symptoms have been reported. The aim of the present study was to clarify the prevalence of elevated serum anti-NMDA receptor antibody titers in patients with new-onset or acute exacerbations of psychiatric symptoms. In addition, the present study aimed to investigate the association between elevated anti-NMDA receptor titers and psychiatric symptoms. METHODS: The present collaborative study included 59 inpatients (23 male, 36 female) presenting with new-onset or exacerbations of schizophrenia-like symptoms at involved institutions from June 2012 to March 2014. Patient information was collected using questionnaires. Anti-NMDA receptor antibody titers were measured using NMDAR NR1 and NR2B co-transfected human embryonic kidney (HEK) 293 cells as an antigen (cell-based assay). Statistical analyses were performed for each questionnaire item. RESULTS: The mean age of participants was 42.0 ± 13.7 years. Six cases had elevated serum anti-NMDA antibody titers (10.2 %), four cases were first onset, and two cases with disease duration >10 years presented with third and fifth recurrences. No statistically significant difference in vital signs or major symptoms was observed between antibody-positive and antibody-negative groups. However, a trend toward an increased frequency of schizophrenia-like symptoms was observed in the antibody-positive group. CONCLUSION: Serum anti-NMDA receptor antibody titers may be associated with psychiatric conditions. However, an association with specific psychiatric symptoms was not observed in the present study. Further studies are required to validate the utility of serum anti-NMDA receptor antibody titer measurements at the time of symptom onset.

Post-Traumatic Stress Symptoms and Burnout Among Medical Rescue Workers 4 Years After the Great East Japan Earthquake: A Longitudinal Study.

OBJECTIVE: This study aimed to evaluate factors associated with post-traumatic stress disorder (PTSD) symptoms and burnout 4 years after the Great East Japan Earthquake among medical rescue workers in Disaster Medical Assistance Teams (DMATs). METHODS: We examined participants' background characteristics, prior health condition, rescue work experiences, and the Peritraumatic Distress Inventory (PDI) score at 1 month after the earthquake. Current psychological condition was assessed by the Impact of Event Scale-Revised and Maslach Burnout Inventory administered 4 years after the earthquake. By applying univariate and multivariate linear regression analyses, we assessed the relative value of the PDI and other baseline variables for PTSD symptoms and burnout at 4 years after the earthquake. RESULTS: We obtained baseline data from 254 participants during April 2 to 22, 2011. Of the 254 participants, 188 (74.0%) completed the follow-up assessment. PDI score 1 month after the earthquake was associated with symptoms of PTSD (ß=0.35, P<.01) and burnout (ß=0.21, P<.01). Stress before deployment was a related factor for burnout 4 years after the earthquake in these medical rescue workers (ß=2.61, P<.04). CONCLUSIONS: It seems important for DMAT headquarters to establish a routine system for assessing the PDI of medical rescue workers after deployment and screen those workers who have high stress prior to deployment (Disaster Med Public Health Preparedness. 2016;10:848-853).

Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3.

Osteoarthritis is a common debilitating joint disorder. Risk factors for osteoarthritis include age, which is associated with thinning of articular cartilage. Here we generate chondrocyte-specific salt-inducible kinase 3 (Sik3) conditional knockout mice that are resistant to osteoarthritis with thickened articular cartilage owing to a larger chondrocyte population. We also identify an edible Pteridium aquilinum compound, pterosin B, as a Sik3 pathway inhibitor. We show that either Sik3 deletion or intraarticular injection of mice with pterosin B inhibits chondrocyte hypertrophy and protects cartilage from osteoarthritis. Collectively, our results suggest Sik3 regulates the homeostasis of articular cartilage and is a target for the treatment of osteoarthritis, with pterosin B as a candidate therapeutic.

Generation of scaffoldless hyaline cartilaginous tissue from human iPSCs.

Defects in articular cartilage ultimately result in loss of joint function. Repairing cartilage defects requires cell sources. We developed an approach to generate scaffoldless hyaline cartilage from human induced pluripotent stem cells (hiPSCs). We initially generated an hiPSC line that specifically expressed GFP in cartilage when teratoma was formed. We optimized the culture conditions and found BMP2, transforming growth factor ß1 (TGF-ß1), and GDF5 critical for GFP expression and thus chondrogenic differentiation of the hiPSCs. The subsequent use of scaffoldless suspension culture contributed to purification, producing homogenous cartilaginous particles. Subcutaneous transplantation of the hiPSC-derived particles generated hyaline cartilage that expressed type II collagen, but not type I collagen, in immunodeficiency mice. Transplantation of the particles into joint surface defects in immunodeficiency rats and immunosuppressed mini-pigs indicated that neocartilage survived and had potential for integration into native cartilage. The immunodeficiency mice and rats suffered from neither tumors nor ectopic tissue formation. The hiPSC-derived cartilaginous particles constitute a viable cell source for regenerating cartilage defects.

Modeling type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cells.

Type II collagen is a major component of cartilage. Heterozygous mutations in the type II collagen gene (COL2A1) result in a group of skeletal dysplasias known as Type II collagenopathy (COL2pathy). The understanding of COL2pathy is limited by difficulties in obtaining live chondrocytes. In the present study, we converted COL2pathy patients' fibroblasts directly into induced chondrogenic (iChon) cells. The COL2pathy-iChon cells showed suppressed expression of COL2A1 and significant apoptosis. A distended endoplasmic reticulum (ER) was detected, thus suggesting the adaptation of gene expression and cell death caused by excess ER stress. Chondrogenic supplementation adversely affected the chondrogenesis due to forced elevation of COL2A1 expression, suggesting that the application of chondrogenic drugs would worsen the disease condition. The application of a chemical chaperone increased the secretion of type II collagen, and partially rescued COL2pathy-iChon cells from apoptosis, suggesting that molecular chaperons serve as therapeutic drug candidates. We next generated induced pluripotent stem cells from COL2pathy fibroblasts. Chondrogenically differentiated COL2pathy-iPS cells showed apoptosis and increased expression of ER stress-markers. Finally, we generated teratomas by transplanting COL2pathy iPS cells into immunodeficient mice. The cartilage in the teratomas showed accumulation of type II collagen within cells, a distended ER, and sparse matrix, recapitulating the patient's cartilage. These COL2pathy models will be useful for pathophysiological studies and drug screening.

iPS cell technologies and cartilage regeneration.

Articular cartilage covers the ends of bone and provides shock absorption and lubrication to the diarthrodial joints. Cartilage has a limited capacity for repair when injured, and there is a need for cell sources for chondrocytes that can be transplanted as part of a regenerative medicine approach. Induced pluripotent stem cells (iPSCs) have pluripotency and the potential for self-renewal similar to embryonic stem cells (ESCs), but are not associated with the ethical issues that have plagued ESCs. Recent progress has made it possible to generate integration-free iPSCs and to differentiate iPSCs toward chondrocytes. An iPSC library prepared from donors homozygous for common HLA types is being developed, and will be able to provide allogeneic iPSC-derived chondrocytes at low cost that can cover the majority of the population. As an alternative approach, chondrocytic cells can be induced directly from dermal fibroblasts without going through the iPSC stage. Another important application of the iPSC technology is modeling cartilage diseases, such as skeletal dysplasia. Chondrogenically differentiated iPSCs generated from patients would recapitulate the pathology, and may serve as a useful platform both for exploring the disease mechanisms and for drug screening. This article is part of a Special Issue entitled "Stem Cells and Bone".

Statin treatment rescues FGFR3 skeletal dysplasia phenotypes.

Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here we show that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. We converted fibroblasts from thanatophoric dysplasia type I (TD1) and ACH patients into iPSCs. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH.

Direct induction of chondrogenic cells from human dermal fibroblast culture by defined factors.

The repair of large cartilage defects with hyaline cartilage continues to be a challenging clinical issue. We recently reported that the forced expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) can induce chondrogenic cells from mouse dermal fibroblast culture without going through a pluripotent state. We here generated induced chondrogenic (iChon) cells from human dermal fibroblast (HDF) culture with the same factors. We developed a chondrocyte-specific COL11A2 promoter/enhancer lentiviral reporter vector to select iChon cells. The human iChon cells expressed marker genes for chondrocytes but not fibroblasts, and were derived from non-chondrogenic COL11A2-negative cells. The human iChon cells formed cartilage but not tumors in nude mice. This approach could lead to the preparation of cartilage directly from skin in human, without going through pluripotent stem cells.