Takuya Higashino

Adipose tissue remodeling under ischemia: death of adipocytes and activation of stem/progenitor cells.

Background: Following various types of plastic surgery, such as adipose grafting and flap elevation, adipose tissue undergoes ischemia, leading to hypoxia and nutrient depletion. However, few studies have examined ischemic and/or hypoxic changes in adipose tissue. Methods: The authors established surgically induced ischemia models by severing blood vessels supplying the inguinal fat pads in mice. The partial pressure of oxygen in adipose tissue was measured with an oxygen monitor, and ischemic changes were analyzed by whole-mount staining, immunohistochemistry, flow cytometry, and Western blotting. The authors also examined cell survival under a hypoxic condition in vitro. Results: Models for three degrees (mild, intermediate, and severe) of ischemia showed approximately 75, 55, and 20 percent of the partial pressure of oxygen level in normal adipose tissue (50.5 ± 1.3 mm Hg), respectively. Adipose tissue atrophy with substantial fibrosis on day 28 was seen, depending on the severity of ischemia. Intermediate and severe ischemia induced elevated expression of hypoxia-inducible factor 1&agr; and fibroblast growth factor 2 on day 1 and degenerative changes (i.e., apoptosis, necrosis, and macrophage infiltration and phagocytosis) in adipose tissue. Dead cells included adipocytes, vascular endothelial cells, and blood-derived cells, but not adipose-derived stem/progenitor cells. Subsequent to degenerative changes, regenerative changes were seen, including angiogenesis, adipogenesis, and proliferation of cells (adipose-derived stem/progenitor cells, vascular endothelial cells, and blood cells). The authors found that, in vitro, the experimentally differentiated adipocytes underwent apoptosis and/or necrosis under severe hypoxia, but adipose-derived stem/progenitor cells remained viable. Conclusions: Severe ischemia/hypoxia induces degenerative changes in adipose tissue and subsequent adaptive tissue remodeling. Adipocytes die easily under ischemic conditions, whereas adipose-derived stem/progenitor cells are activated and contribute to adipose tissue repair.

Ultrasound assessment of deep tissue injury in pressure ulcers: possible prediction of pressure ulcer progression.

Background: The concept of deep tissue injury under intact skin helps us understand the pathogenesis of pressure ulcers, but the best method for detecting and evaluating deep tissue injury remains to be established. Methods: Intermediate-frequency (10-MHz) ultrasonography was performed to evaluate deep tissue injury. The authors analyzed 12 patients (nine male patients and three female patients aged 16 to 92 years) who showed deep tissue injury–related abnormal findings on ultrasonography at the first examination and were followed up until the pressure ulcer reached a final stage. Results: The stage of ulcer worsened in six of 12 cases compared with baseline, and healed in the remaining six patients. The authors recognized four types of abnormal signs unique to deep tissue damage in ultrasonography: unclear layered structure, hypoechoic lesion, discontinuous fascia, and heterogeneous hypoechoic area. Unclear layered structure, hypoechoic lesion, discontinuous fascia, and heterogeneous hypoechoic area were detected at the first examination in 12, 10, seven, and five patients, respectively. Unclear layered structure and hypoechoic lesion were more commonly seen in pressure ulcers in deep tissue injury than the other features, but the follow-up study suggested that discontinuous fascia and heterogeneous hypoechoic area are more reliable predictors of future progression of pressure ulcers. Conclusions: The use of intermediate-frequency ultrasound reliably identified deep tissue injury and was believed to contribute to prevention and treatment of pressure-related ulcers. The results suggest that specific ultrasonographic characteristics may predict which pressure ulcers will progress.

Treatment of lymphedema with lymphaticovenular anastomoses.

Although lymphedema in the extremities is a troublesome adverse effect following radical resection of various cancers, conventional therapies for lymphedema are not always satisfactory, and new breakthroughs are anticipated. With the introduction of supermicrosurgical techniques for the anastomosis of blood or lymphatic vessels less than 0.8 mm in diameter, we have developed a novel method of lymphaticovenular anastomosis for the treatment of primary as well as secondary lymphedema in the extremities. Here, we review the pathophysiological aspects of lymphedema, emphasizing the importance of smooth-muscle cell function in the affected lymphatic walls. We then describe the theoretical basis and detailed operative techniques of our lymphaticovenular anastomoses. Although technically demanding, especially for beginners, we believe that this method will become a new clinical standard for the treatment of lymphedema in the near future.

Adipose injury-associated factors mitigate hypoxia in ischemic tissues through activation of adipose-derived stem/progenitor/stromal cells and induction of angiogenesis.

Based on the analysis of exudates from injured adipose tissue, we prepared a mixture containing the injury-associated growth factors at the same proportion as the exudates, named adipose injury cocktail (AIC). We hypothesized that AIC induces a series of regenerating and angiogenic processes without actual wounding. The purpose of this study is to elucidate the therapeutic potentials of AIC. AIC preferentially activated adipose-derived stem/progenitor/stromal cells (ASCs) to proliferate, migrate, and form networks compared with vascular endothelial cells, whereas vascular endothelial growth factor did not induce mitogenesis or chemotaxis in human ASCs. Each component growth factor of AIC was differently responsible for the ASC activation. AIC-treated ASCs tended to differentiate into adipocytes or vessel-constituting cells rather than into other cell types. In ischemic adipose tissues of mice, induced by either a surgical intervention or diabetes, AIC administration enhanced proliferation, especially of CD31(-)/CD34(+) ASCs, and mitigated tissue hypoxia by increasing capillary density and reducing fibrogenesis. These results suggest that AIC may have therapeutic potentials for various ischemic/hypoxic conditions by inducing adipose remodeling and neovascularization through activation of ASCs and other cells. Treatment with AIC has many advantages over cell-based therapies regarding morbidity, cost, and physical risks and may be used as an alternative therapy for improving tissue oxygen.

Adipose tissue remodeling in lipedema: adipocyte death and concurrent regeneration

Lipedema is a disease with unknown etiology presenting as bilateral and symmetric enlargement of the lower extremities due to subcutaneous deposition of the adipose tissue. Here we describe the histopathological features of the lipedema tissue and nonaffected adipose tissue obtained from a typical patient with severe lipedema. Immunohistochemical analyses indicated degenerative and regenerative changes of the lipedema tissue, characterized by crown‐like structures (necrotizing adipocytes surrounded by infiltrating CD68+ macrophages; a feature commonly seen in obese adipose tissue) and proliferation of adipose‐derived stem/progenitor/stromal cells (Ki67+CD34+ cells), respectively. These findings suggested increased adipogenesis in the lipedema tissue, which may further lead to hypoxia similar to that seen in obesity, resulting in adipocyte necrosis and macrophage recruitment. The confinement to the lower extremities and the difference from systemic obesity warrants further elucidation in future studies.

A Prospective Randomized Controlled Study of Oral Tranexamic Acid for Preventing Postinflammatory Hyperpigmentation After Q-Switched Ruby Laser

BACKGROUND Postinflammatory hyperpigmentation (PIH) is the most common skin complication in Asians after invasive cosmetic treatments. OBJECTIVE To determine whether oral tranexamic acid (TA) reduces the incidence of PIH after Q‐switched ruby laser (QSRL) treatment. METHODS AND MATERIALS Thirty‐two Japanese women underwent QSRL treatment for senile lentigines on the face. They were randomly divided into two groups that did (n=15) and did not (n=17) receive oral TA treatment (750 mg/d) for the first 4 weeks after QSRL treatment. Nineteen participants had melasma‐like maculae at baseline. Clinical and colorimetric assessments were performed at baseline and 2 and 4 weeks later. RESULTS Pigmentation was effectively treated using QSRL at 2 weeks, but PIH was frequently seen at 4 weeks. There was no significant difference in the incidence of PIH between participants who received oral TA and those who did not. The presence of melasma did not influence the effectiveness of the treatment. CONCLUSION Although oral TA has been reported to have depigmentation effects, it may not be effective for preventing PIH after QSRL. Considering the dosage and duration of treatment, an optimal protocol may be needed to induce the efficacy of this treatment to achieve the PIH‐preventing effect of oral TA. The authors have indicated no significant interest with commercial supporters.

Cellular and molecular features of lipoma tissue: comparison with normal adipose tissue

Background  Involvement of adipose‐derived stem/progenitor/stromal cells (ASCs) in the development of lipomas has been suggested, but the pathogenesis and pathophysiology of this tumour remain unclear.

Tissue reactions to cog structure and pure gold in lifting threads: a histological study in rats.

BACKGROUND Thread lifting has become popular as a minimally-invasive suspension procedure, but there is little basic and clinical evidence in the literature on the long-term effects. OBJECTIVES The authors investigate the effects of two types of lifting threads in a rat model over the course of seven months. METHODS The dorsal skin of 18 Wistar rats was implanted with a 20-mm fragment of one of three types of thread: nonabsorbable monofilament cog, pure gold (24 karat) with no cog, and pure gold-coated cog. Six rats were in each group. Tissue samples were harvested and histologically evaluated at one, three, and seven months. RESULTS Histological assessment indicated (1) acute tissue reactions to the regular cog thread involving myofibroblasts and (2) delayed tissue reactions to the pure gold thread involving giant cells. The gold-coated cog thread showed a combination of the histological reactions associated with the cog thread and the pure gold thread, including faint early reactions, strong delayed reactions, and long-lasting capsule formation. Notably, the gold coating gradually came loose from the thread surface, suggesting that the release of tiny gold particles may promote longer-lasting tissue reactions. CONCLUSIONS The combination of cog structure and pure gold coating was evaluated for the first time in this study and results suggest that the gold-coated cog thread has clinical potential.

Combination of thermographic and ultrasonographic assessments for early detection of deep tissue injury

Early detection and intervention of deep tissue injury are important to lead good outcome. Although the efficiency of ultrasonographic assessment of deep tissue injury has been reported previously, it requires a certain level of skill for accurate assessment. In this study, we present an investigation of the combination of thermographic and ultrasonographic assessments for early detection of deep tissue injury. We retrospectively reviewed 28 early‐stage pressure ulcers (21 patients) presenting at the University of Tokyo Hospital between April 2009 and February 2010, surveying the associated thermographic and ultrasonographic findings. The wound temperature patterns were divided into low, even and high compared with the surrounding skin. Ultrasonographic findings were classified into unclear layer structure, hypoechoic lesion, discontinuous fascia and heterogeneous hypoechoic area. All 13 ulcers that were associated with low temperature showed good outcome; three ulcers had even temperatures and 12 ulcers showed high temperature on thermographic assessment. The two deep tissue injuries were rated high on thermographic assessment and showed heterogeneous hypoechoic area findings on ultrasonographic assessment. No non‐deep tissue injury lesion was associated with these two findings simultaneously. The combination of thermographic and ultrasonographic assessments is expected to increase the accuracy of the early detection of deep tissue injuries.

Clinically applicable transplantation procedure of dermal papilla cells for hair follicle regeneration.

Dermal papilla cells (DPCs) interact with epithelial stem cells and induce hair folliculogenesis. Cell‐based therapies using expanded DPCs for hair regeneration have been unsuccessful in humans. Two major challenges remain: first, expanded DPCs obtained from adult hair follicles have functional limitations; second, a clinically applicable method is needed for transplanting DPCs. This study aimed to identify an efficient, minimally invasive and economical DPC transplantation procedure for use in clinical settings. Five clinically applicable transplantation procedures were tested, termed the Pinhole, Laser, Slit, Non‐vascularized sandwich (NVS) and Hemi‐vascularized sandwich (HVS) methods. Labelled rat dermal papilla tissue was transplanted into rat sole skin, and hair follicle regeneration was evaluated histologically. Regenerated follicles and labelled DPCs were detected for all methods, although some follicles showed abnormal growth, i.e. a cystic or inverted appearance. The HVS method, pioneered here, resulted in significantly larger number of regenerated follicles that were more mature and regular than those observed using the other methods. Moreover, hair growth was detected after expanded adult‐derived DPC transplantation using the HVS method. These results suggest that direct contact of epithelial and dermal components and better vascularization/oxygenation of the recipient site are critical for hair regeneration in cell‐based therapies. Copyright