Koichiro Kiya

Physiological ER Stress Mediates the Differentiation of Fibroblasts.

Recently, accumulating reports have suggested the importance of endoplasmic reticulum (ER) stress signaling in the differentiation of several tissues and cells, including myoblasts and osteoblasts. Secretory cells are easily subjected to ER stress during maturation of their secreted proteins. Skin fibroblasts produce and release several proteins, such as collagens, matrix metalloproteinases (MMPs), the tissue inhibitors of metalloproteinases (TIMPs) and glycosaminoglycans (GAGs), and the production of these proteins is increased at wound sites. Differentiation of fibroblasts into myofibroblasts is one of the key factors for wound healing and that TGF-β can induce fibroblast differentiation into myofibroblasts, which express α-smooth muscle actin. Well-differentiated myofibroblasts show increased production of collagen and TGF-β, and bring about wound healing. In this study, we examined the effects of ER stress signaling on the differentiation of fibroblasts, which is required for wound healing, using constitutively ER stress-activated primary cultured fibroblasts. The cells expressed positive α-smooth muscle actin signals without TGF-β stimulation compared with control fibroblasts. Gel-contraction assays suggested that ER stress-treated primary fibroblasts caused stronger shrinkage of collagen gels than control cells. These results suggest that ER stress signaling could accelerate the differentiation of fibroblasts to myofibroblasts at injured sites. The present findings may provide important insights for developing therapies to improve wound healing.

Simultaneous correction of deviated columella and wide nostril floor using the Y-V advancement in unilateral cleft lip nasal deformities.

Here, we describe an operative method for the simultaneous correction of deviated columella and wide nostril floor in unilateral cleft lip nasal deformities. The V-shaped flap of the affected nostril floor was inserted into the side wall of the columella using the Y-V advancement. By suturing the anterocaudal septum, which is often deviated to the unaffected side, with the subcutaneous tissue of the affected alar base, it was possible to simultaneously reposition the columellar base in the midline as well as narrow the wide nostril floor. This method was technically simple, with low invasiveness for the septal cartilage. Furthermore, as noted in one of the two cases described, it would enable the reconstruction of the natural shape of the nostril sill.

A novel pre-surgical maxillary orthodontic device using β-titanium wire for wide unilateral cleft lip and palate patients : preliminary study of its efficacy and impact for the maxillary formation

BACKGROUND AND AIM For patients with a wide, complete, unilateral cleft lip and palate, pre-surgical maxillary orthodontic treatments have been used to reduce the alveolar gap before cheiloplasty. However, most of these treatments are complicated and laborious for patients and for medical professionals. Thus, we developed an original pre-surgical orthodontic device made with two separate acrylic resin plates connected with a spring-shaped β-titanium wire (β-TW). When the device was applied on the palate, each segment of the maxilla was automatically aligned for our target formation with the elastic force of β-titanium alloy. This study aimed to evaluate the efficacy of the new device and the size of the maxilla in comparison with the conventional Hotz procedures. PATIENTS AND METHODS A total of 47 patients with a wide unilateral cleft lip and palate were retrospectively evaluated; 33 patients were treated with our new device (β-TW plate group) and 14 were treated with a Hotz plate (HP group). We evaluated the alveolar gap reduction and the size of the maxilla between the two groups, obtaining intraoral maxillary impressions at birth, at 3 months and 1 year. RESULTS The width of the alveolar gap in the β-TW plate group was significantly reduced compared with that in the HP group 1 month after the treatment (p < 0.001). The alveolar gap reduction continued until the age of 1 year (p = 0.02). By contrast, no significant difference in the maxillary size was observed between the two groups at any examination period. CONCLUSION Our treatment protocol using the β-TW plate was not only easy and simple to apply but it was also cost-effective, with highly predictable outcomes. Moreover, it provided the ideal alveolar cleft reduction without detrimental collapse of the alveolar segments. Therefore, we consider our β-TW plate device to be useful for application in pre-surgical orthodontic treatments.

Endothelial cell-derived endothelin-1 is involved in abnormal scar formation by dermal fibroblasts through RhoA/Rho-kinase pathway

Hypertrophic scars and keloids are characterized by excessive dermal deposition of extracellular matrix due to fibroblast‐to‐myofibroblast differentiation. Endothelin‐1 (ET‐1) is primarily produced by vascular endothelial cells and plays multiple roles in the wound‐healing response and organ fibrogenesis. In this study, we investigated the pathophysiological significance of ET‐1 and involvement of RhoA, a member of the Rho GTPases, in hypertrophic scar/keloid formation. We found that ET‐1 expression on dermal microvascular endothelial cells (ECs) in hypertrophic scars and keloids was higher than that in normal skin and mature scars. We also confirmed that ET‐1 induced myofibroblast differentiation and collagen synthesis in cultured human dermal fibroblasts through the RhoA/Rho‐kinase pathway. Finally, since hypertrophic scar/keloid formation was most prominent in areas exposed to mechanical stretch, we examined how mechanical stretch affected ET‐1 secretion in human dermal microvascular ECs, and found that mechanical stretch increased ET‐1 gene expression and secretion from ECs. Taken together, these results suggest that dermal microvascular ECs release ET‐1 in response to mechanical stretch, and thereby contribute to the formation of hypertrophic scars and keloids through the RhoA/Rho‐kinase pathway.

A novel active intraoral appliance for presurgical orthopaedic treatment in patients with complete bilateral cleft lip and palate

BACKGROUND Management of the protruding/deviated premaxilla in patients with complete bilateral cleft lip and palate is a challenging problem for surgeons and orthodontists. Various passive and active methods have been developed for the presurgical orthopaedic treatment. However, most of these treatments are complicated and laborious for the patients parents and clinicians. Here, we describe our original active intraoral appliance comprising two components, that is, the premaxillary and palatine process plates, connected with two elastic chains, and we assess its therapeutic efficacy. PATIENTS AND METHODS We retrospectively evaluated 15 patients treated using this appliance during 2006-2012, followed up for an average of 60.3 months (range, 18-97 months). We analysed the cleft widths and maxillary size, obtained pretreatment, post-treatment and pre-palatoplasty. RESULTS Cleft widths and premaxillary protrusion were significantly decreased post treatment; however, the transverse dimensions were not significantly altered. In all cases, the protruding/deviated premaxilla was set into a suitable position within 1 month, and we could perform one-stage cheiloplasty using the modified Mulliken method with low tension. CONCLUSION Our appliance is technically simple to use, less invasive to the skin and bone and cost-effective, with reliable and predictable outcomes. In the follow-up period, we observed no detrimental growth of the maxilla or dentition. Therefore, we consider our appliance to be useful for application in presurgical orthopaedic treatments of complete bilateral cleft lip and palate.

Cutaneous resurfacing around a permanent tracheostoma with an internal mammary artery perforator flap

Abstract When soft tissue reconstruction near a permanent tracheostoma is needed, transfer of a thin and pliable flap is preferable in order to avoid occlusion of the newly created tracheostomal opening. Although microsurgical fasciocutaneous flap transfer may be desirable for such reconstruction, it is not always an option due to lack of recipient vessels for vascular anastomosis or a patient’s poor medical condition that would prohibit a lengthy procedure. An alternative option is the internal mammary artery perforator flap, which is easy to elevate, has a long arc of rotation, and has a reliable blood supply. Here, we report three cases of cutaneous resurfacing around a permanent tracheostoma with an internal mammary artery perforator flap.

Hydroxyapatite implantation for the repair of a congenital nasal anomaly: 10 years follow-up

Abstract Frontonasal dysplasia is a rare congenital anomaly characterized by ocular hypertelorism, a broad nasal root, and vertical median cleft of the nose and/or upper lip and palate. We report a case of frontonasal dysplasia in which hydroxyapatite was used to treat a nasal deformity in early childhood. In the 10 years of follow-up of our case, there were no complications such as infection, malpositioning, or exposure, and computed tomography revealed no resorption or malpositioning of the implant. Hydroxyapatite implants may be a viable alternative to autologous bone/cartilage grafts for the repair of congenital nasal anomalies until nasal development is completed.

Differentiated adipose-derived stem cells promote the recovery of nociceptor function in rats.

The loss of nociceptive function in the skin because of trauma or surgery can impair the quality of life. The recovery of nociceptor function is mediated by two different axonal responses: nerve growth factor (NGF)-dependent collateral sprouting of undamaged nerves and NGF-independent regeneration of damaged nerves. We reported previously that adipose-derived stem cells (ASCs) can transdifferentiate into Schwann cell (SC)-like cells (dASCs) and that transplantation of dASCs increases axonal density in skin flaps. In the present study, we used an animal model that allowed for the individual assessment of collateral sprouting and regeneration. In-vitro differentiation of ASCs to dASCs significantly increased the production of NGF and brain-derived neurotrophic factor (BDNF) to levels comparable with SCs. In-vivo experiments showed that dASC and SC transplantation significantly increased the area of the mechano-nociceptive field in both collateral sprouting and regeneration models, whereas ASC transplantation exerted no significant effect. Antibody blocking experiment showed that these effects of dASC transplantation in the regeneration model were partly mediated by BDNF. Interestingly, the final areas of nociceptive fields between the two experimental models did not differ significantly for any treatment condition. These results indicate that dASC transplantation differentially facilitates collateral sprouting and axonal regeneration by delivering NGF and other neurotrophic factors (e.g. BDNF), respectively. Although there is a limit to nociceptive field enlargement irrespective of axonal response, dASC transplantation could present a new approach for improving nociceptive function in denervated skin.