研究者詳細 - 池ノ上　学

論文 - 池ノ上　学

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Epigenetic Changes in Neonates Born to Mothers With Gestational Diabetes Mellitus May Be Associated With Neonatal Hypoglycaemia

Kasuga Y., Kawai T., Miyakoshi K., Saisho Y., Tamagawa M., Hasegawa K., Ikenoue S., Ochiai D., Hida M., Tanaka M., Hata K.

Frontiers in Endocrinology （Frontiers in Endocrinology） 12 690648 - 690648 2021年06月

ISSN 1664-2392

The detection of epigenetic changes associated with neonatal hypoglycaemia may reveal the pathophysiology and predict the onset of future diseases in offspring. We hypothesized that neonatal hypoglycaemia reflects the in utero environment associated with maternal gestational diabetes mellitus. The aim of this study was to identify epigenetic changes associated with neonatal hypoglycaemia. The association between DNA methylation using Infinium HumanMethylation EPIC BeadChip and neonatal plasma glucose (PG) level at 1 h after birth in 128 offspring born at term to mothers with well-controlled gestational diabetes mellitus was investigated by robust linear regression analysis. Cord blood DNA methylation at 12 CpG sites was significantly associated with PG at 1 h after birth after adding infant sex, delivery method, gestational day, and blood cell compositions as covariates to the regression model. DNA methylation at two CpG sites near an alternative transcription start site of ZNF696 was significantly associated with the PG level at 1 h following birth (false discovery rate-adjusted P < 0.05). Methylation levels at these sites increased as neonatal PG levels at 1 h after birth decreased. In conclusion, gestational diabetes mellitus is associated with DNA methylation changes at the alternative transcription start site of ZNF696 in cord blood cells. This is the first report of DNA methylation changes associated with neonatal PG at 1 h after birth.

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What are the causes for low birthweight in Japan? A single hospital-based study

Kasuga Y., Ikenoue S., Tamagawa M., Oishi M., Endo T., Sato Y., Iida M., Sato Y., Tanaka M., Ochiai D.

PLoS ONE （PLoS ONE） 16 （ 6 June ） e0253719 2021年06月

Low-birthweight (LBW; <2,500 g) babies are at a higher risk of poor educational achievement, disability, and metabolic diseases than normal-birthweight babies in the future. However, reliable data on factors that contribute to LBW have not been considered previously. Therefore, we aimed to examine the distribution of the causes for LBW. A retrospective review of cases involving 4,224 babies whose mothers underwent perinatal care at Keio University Hospital between 2013 and 2019 was conducted. The LBW incidence was 24% (1,028 babies). Of the 1,028 LBW babies, 231 babies were from multiple pregnancies. Of the 797 singleton LBW babies, 518 (65%) were born preterm. Obstetric complications in women with preterm LBW babies included premature rupture of membrane or labor onset (31%), hypertensive disorders of pregnancy (HDP, 64%), fetal growth restriction (24%), non-reassuring fetal status (14%), and placental previa/vasa previa (8%). Of the 279 term LBW babies, 109 (39%) were small for gestational age. Multiple logistic regression analyses revealed the following factors as LBW risk factors in term neonates: low pre-pregnancy maternal weight, inadequate gestational weight gain, birth at 37 gestational weeks, HDP, anemia during pregnancy, female sex, and neonatal congenital anomalies. HDP was an LBW risk factor not only in preterm births but also in term births. Our results suggest that both modifiable and non-modifiable factors are causes for LBW. It may be appropriate to consider a heterogeneous rather than a simple classification of LBW and to evaluate future health risks based on contributing factors.

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A case of abdominal compartment syndrome caused by amniotic fluid embolism treated with ABTHERA™ therapy: World's first report in the obstetric field

Hirata M., Hasegawa K., Kasuga Y., Haiden A., Ikenoue S., Yamamoto R., Tanaka M., Sasaki J., Ochiai D.

Taiwanese Journal of Obstetrics and Gynecology （Taiwanese Journal of Obstetrics and Gynecology） 60 （ 3 ） 579 - 580 2021年05月

ISSN 10284559

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胎児心循環機能のモニタリングによる周産期管理を実施した高拍出性心不全を呈した胎児巨大肝血管腫の1例

林彩世, 小澤克典, 室本仁, 杉林里佳, 小杉洋平, 柴田優花, 池ノ上学, 和田誠司, 伊藤裕司, 左合治彦

超音波医学（(公社)日本超音波医学会） 48 （ 3 ） 133 - 137 2021年05月

ISSN 1346-1176

胎児巨大肝血管腫は動静脈シャントによって高拍出性心不全を呈し,胎盤循環も悪化する.そのため胎盤循環を含めた胎児循環の評価を行い適切な娩出時期を決定する必要があるが,いまだ確立した評価方法がない.臍静脈血流量(UVFV)の総心拍出量(CCO)における割合(UVFV/CCO)は胎盤循環の指標となることが報告されており,この指標を含めた心循環機能評価を行うことで早期に病状の変化をとらえた胎児巨大肝血管腫の症例を報告する.妊娠27週に心胸郭断面積比(CTAR)48.5%の心拡大と軽度の僧帽弁・三尖弁逆流を認めた.CCO 1,214ml/min,UVFV 350ml/minと増加を認めたが,UVFV/CCOは28.9%と保たれ,羊水量は正常で胎児水腫を認めなかった.しかし,妊娠30週1日にCTAR 62.9%と増悪,CCO 1,620ml/min,UVFV 236ml/minとなり,UVFV/CCOは14.6%に低下した.胎児水腫は認めなかったが羊水過少となり,Biophysical profiling score 2/10点と低値であった.妊娠30週4日に胎児心拍数陣痛図において基線細変動の減少が出現し,胎児機能不全と診断,緊急帝王切開術を施行した.児は2,340g,Apgar score 1点(1分値),5点(5分値),臍帯動脈血pH 7.254で出生した.日齢1.5に肝血管腫に対してコイル塞栓術を行ったが原病のコントロールがつかず,グラム陽性球菌による敗血症で日齢70に永眠した.UVFV/CCOの減少が巨大肝血管腫による胎児胎盤循環の悪化を反映すると思われた.(著者抄録)

帝王切開術後の腹腔内出血に対し、腹部コンパートメント症候群に準じて治療介入した1例

大石真希, 落合大吾, 春日義史, 田中雄也, 玉川真澄, 遠藤豊英, 佐藤佑, 池ノ上学, 田中守, 青木大輔

東京産科婦人科学会会誌（(一社)東京産科婦人科学会） 70 （ 2 ） 231 - 236 2021年04月

ISSN 2186-0599

産科領域における腹部コンパートメント症候群(abdominal compartment syndrome:ACS)の報告は稀である。今回我々は、帝王切開術後に腹腔内出血を認め、ACSに準じて加療した症例を経験した。症例は43歳、妊娠39週0日に分娩中に児の持続徐脈を認め、超緊急帝王切開術を施行し常位胎盤早期剥離と診断した。帰室1時間後、出血性ショック状態のため産科危機的出血を宣言し子宮動脈塞栓術を施行した。術後1日目、著明な腹部膨隆を認め、ACSを疑い腹部造影CT検査を行ったが臓器血流障害は認めなかった。また、膀胱内圧は14mmHgと上昇しており、約4Lの血性腹水を経腹的にドレナージしたところ呼吸状態が劇的に改善した。そして、その後の経過は順調で術後7日目に退院した。ACS疑いの症例では、腹腔内圧の推定には膀胱内圧が有用であり、早期の治療介入が病態改善に寄与する可能性が示唆された。(著者抄録)

Placental Corticotrophin-Releasing Hormone is a Modulator of Fetal Liver Blood Perfusion

Ikenoue S., Waffarn F., Ohashi M., Tanaka M., Gillen D.L., Buss C., Entringer S., Wadhwa P.D.

Journal of Clinical Endocrinology and Metabolism （Journal of Clinical Endocrinology and Metabolism） 106 （ 3 ） 646 - 653 2021年03月

ISSN 0021972X

Context: Variation in fetal liver blood flow influences fetal growth and postnatal body composition. Placental corticotrophin-releasing hormone has been implicated as a key mediator of placental-fetal perfusion. Objective: To determine whether circulating levels of placental corticotrophin-releasing hormone across gestation are associated with variations in fetal liver blood flow. Design: Prospective cohort study. Methods: Fetal ultrasonography was performed at 30 weeks' gestation to characterize fetal liver blood flow (quantified by subtracting ductus venosus flow from umbilical vein flow). Placental corticotrophin-releasing hormone was measured in maternal circulation at approximately 12, 20, and 30 weeks' gestation. Multiple regression analysis was used to determine the proportion of variation in fetal liver blood flow explained by placental corticotrophin-releasing hormone. Covariates included maternal age, parity, pre-pregnancy body mass index, gestational weight gain, and fetal sex. Results: A total of 79 uncomplicated singleton pregnancies were analyzed. Fetal liver blood flow was 68.4 ± 36.0 mL/min (mean ± SD). Placental corticotrophin-releasing hormone concentrations at 12, 20, and 30 weeks were 12.5 ± 8.1, 35.7 ± 24.5, and 247.9 ± 167.8 pg/mL, respectively. Placental corticotrophin-releasing hormone at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fetal liver blood flow at 30 weeks (r = 0.319; P = 0.004) and explained 10.4% of the variance in fetal liver blood flow. Conclusions: Placental corticotrophin-releasing hormone in late gestation is a possible modulator of fetal liver blood flow and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

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Defining the normal growth curve of fetal fractional limb volume in a japanese population

Ikenoue S., Akiba Y., Endo T., Kasuga Y., Yakubo K., Ishii R., Tanaka M., Ochiai D.

Journal of Clinical Medicine （Journal of Clinical Medicine） 10 （ 3 ） 1 - 9 2021年02月

ISSN 2077-0383

Fetal fractional limb volume is a useful measure for predicting birth weight and newborn adiposity; however, a normal growth curve has been reported solely in the United States. As the birth weight of neonates in Japan is significantly lower than that in the US, fetal fractional limb volume is likely to be smaller in the Japanese population. This study aimed to define the normal growth curve of fractional arm volume (AVol) and thigh volume (TVol) in the Japanese population. Ultrasound scans of 453 AVol and TVol pairs were obtained; each AVol and TVol percentile at each gestational age was calculated. The measured AVol and TVol at each gestational week were also converted to z-scores based on a previous report. The growth curves increased linearly until the second trimester and exponentially in the third trimester. Linear regression showed a significant negative correlation between gestational age and AVol and TVol z-scores. The growth pattern of fetal fractional limb volume in the Japanese population is consistent with, but smaller than, that reported in the US; this difference becomes greater as the gestational age progresses.

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Cell sheets using human amniotic fluid stem cells reduce tissue fibrosis in murine full-thickness skin wounds

Ochiai D., Abe Y., Fukutake M., Sato Y., Ikenoue S., Kasuga Y., Masuda H., Tanaka M.

Tissue and Cell （Tissue and Cell） 68 101472 - 101472 2021年02月

ISSN 00408166

The use of mesenchymal stem cell sheets is a promising strategy for skin regeneration. The injection of dissociated human amniotic fluid stem cells (hAFSCs) was recently found to accelerate cutaneous wound healing with reduced fibrotic scarring, similar to fetal wound healing. However, the use of hAFSCs in applications of cell sheet technology remains limited. The aim of this study was to determine the in vivo efficacy of in vitro-cultured hAFSC sheets in wound healing. The cell sheets were characterized by immunohistochemistry and RT-qPCR and grafted onto full-thickness wounds in BALB/c mice. The wound size was measured, and re-epithelialization, granulation tissue area, and collagen content of the regenerated wound were analyzed histologically. Although the hAFSC sheet contained abundant extracellular matrix molecules and expressed high levels of anti-fibrotic mediators, its grafting did not affect wound closure or the size of the granulation tissue area. In contrast, the organization of type I collagen bundles in the regenerated wound was markedly reduced, while the levels of type III collagen were increased after implantation of the hAFSC sheet. These results suggest that hAFSC sheets can exert anti-fibrotic properties without delaying wound closure.

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Amniotic fluid stem cells as a novel strategy for the treatment of fetal and neonatal neurological diseases

Abe Y., Ochiai D., Sato Y., Otani T., Fukutake M., Ikenoue S., Kasuga Y., Tanaka M.

Placenta （Placenta） 104 247 - 252 2021年01月

ISSN 01434004

Even in the context of modern medicine, infants with fetal and neonatal neurological diseases such as cerebral palsy and myelomeningocele suffer serious long-lasting impairment due to the irreversible neuronal damage. The promotion of neurologically intact survival in patients with perinatal intractable neurological diseases requires the development of novel strategies. One promising strategy involves the use of human amniotic fluid stem cells (hAFSCs), which have attracted much attention in recent years and are known to exert anti-inflammatory and neuroprotective effects. In recent years, the therapeutic effects of hAFSCs on fetal-neonatal neurological diseases have become evident as per intense research efforts by our group and others. Specifically, hAFSCs administered into the nasal cavity migrated to the brain and controlled local inflammation in a rodent model of neonatal hypoxic-ischemic encephalopathy. In contrast, hAFSCs administered intraperitoneally did not migrate to the brain; they rather formed spheroids in the abdominal cavity, resulting in the suppression of systemic inflammation (including in the brain) via the secretion of anti-inflammatory cytokines in concert with peritoneal macrophages in a rodent model of periventricular leukomalacia. Moreover, studies in a rat model of myelomeningocele suggested that hAFSCs administered in utero secreted hepatocyte growth factor and protected the exposed spinal cord during pregnancy. Importantly, autologous hAFSCs, whose use for fetal-neonatal treatment does not raise ethical issues, can be collected during pregnancy and prepared in sufficient numbers for therapeutic use. This article outlines the results of preclinical research on fetal stem cell therapy, mainly involving hAFSCs, in the context of perinatal neurological diseases.

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A safe delivery system to prevent COVID-19 transmission without negative-pressure isolation delivery rooms: Experience from a hospital with nosocomial outbreak

Kasuga Y., Ochiai D., Tamagawa M., Oishi M., Endo T., Sato Y., Iida M., Ikenoue S., Tanaka M.

Taiwanese Journal of Obstetrics and Gynecology （Taiwanese Journal of Obstetrics and Gynecology） 60 （ 1 ） 183 - 184 2021年01月

ISSN 10284559

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Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study

Akiba Y., Ikenoue S., Endo T., Kasuga Y., Ochiai D., Miyakoshi K., Ishii R., Yakubo K., Tanaka M.

BJOG: An International Journal of Obstetrics and Gynaecology （BJOG: An International Journal of Obstetrics and Gynaecology） 128 （ 2 ） 329 - 335 2021年01月

査読有り, ISSN 14700328

Objective: Fetal fractional limb volume has been proposed as a useful measure for quantifying fetal soft tissue development. The aim of this study was to investigate the growth of fractional arm volume (AVol) and fractional thigh volume (TVol) of fetuses with maternal gestational diabetes (GDM) compared with those of fetuses with normal glucose tolerance (NGT). We hypothesised fetal fractional limb volume would be larger in the GDM group than in the NGT group in late gestation. Design: Exploratory observational study. Setting: Saitama Municipal Hospital. Sample: A total of 165 (125 NGT and 40 GDM) singleton Japanese pregnant women. Methods: AVol and TVol were assessed between 20 and 37 weeks’ gestation as cylindrical limb volumes based on 50% of the fetal humeral or femoral diaphysis length. Women were diagnosed as GDM based on the criteria of the Japan Society of Obstetrics and Gynecology. Main outcome measures: AVol and TVol were compared between women with NGT and those with GDM at each gestational age period (2-week intervals from 20 to 37 weeks’ gestation). Results: Overall, 287 ultrasound scans were performed (NGT group, 205 scans; GDM group, 82 scans). There was no significant difference of AVol between the groups before 32 weeks’ gestation. AVol was significantly larger in the GDM group than in the NGT group after 32 weeks’ gestation (P < 0.05). TVol was not statistically different between the groups across gestation. Conclusions: Detection of variations in fetal AVol may provide greater insight into understanding the origins of altered fetal body proportion in GDM. Tweetable abstract: AVol, but not TVol, is significantly larger in fetuses with GDM than in those with NGT after 32 weeks’ gestation.

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Predictors of later insulin therapy for gestational diabetes diagnosed in early pregnancy

Tamagawa M., Kasuga Y., Saisho Y., Tanaka Y., Hasegawa K., Oishi M., Endo T., Sato Y., Ikenoue S., Tanaka M., Ochiai D.

Endocrine Journal （Endocrine Journal） 68 （ 11 ） 1321 - 1328 2021年

ISSN 09188959

Interventions for gestational diabetes mellitus (GDM), diagnosed in early pregnancy, have been a topic of controversy. This study aimed to elucidate factors that predict patients with GDM diagnosed before 24 gestational weeks (early GDM: E-GDM) who require insulin therapy later during pregnancy. Furthermore, we identified patients whose impaired glucose tolerance should be strictly controlled from early gestation onward. Women diagnosed with GDM were categorized based on the gestational age at diagnosis into E-GDM (n = 388) or late GDM (L-GDM, diagnosed after 24 weeks, n = 340) groups. Clinical features were compared between the groups, and the predictors for insulin therapy was evaluated in the E-GDM group. There were no significant between-group differences in terms of perinatal outcomes (e.g., gestational weeks at delivery, fetal growth, hypertensive disorder of pregnancy), with the exception of the Apgar score at 5 min. Moreover, there was no significant difference in the frequency of insulin therapy during pregnancy between the two groups. Using multiple logistic regression analysis, pre-pregnancy body mass index (BMI) ≥25 kg/m2, a family history of diabetes, and higher fasting plasma glucose (FPG), 1 h-plasma glucose (PG), and 2 h-PG values increased insulin therapy risk during pregnancy in the E-GDM group. Furthermore, since E-GDM patients with abnormal levels of FPG, as well as 1 h-PG or 2 h-PG, and those with pre-pregnancy BMI ≥25 kg/m2 and a family history of diabetes had a higher risk of later insulin therapy during pregnancy, they may require more careful follow-up in the perinatal period.

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Prophylactic therapy with human amniotic fluid stem cells improves long-term cognitive impairment in rat neonatal sepsis survivors

Abe Y., Ochiai D., Sato Y., Kanzaki S., Ikenoue S., Kasuga Y., Tanaka M.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 21 （ 24 ） 1 - 12 2020年12月

ISSN 16616596

A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related morbidity and mortality is desirable. Recently, we reported that prophylactic therapy with human amniotic stem cells (hAFSCs) improved survival in a rat model of lipopolysaccharide (LPS)-induced neonatal sepsis through immunomodulation. Besides improving the mortality, increasing survival without major morbidities is an important goal of neonatal intensive care for neonatal sepsis. This study investigated long-term neurological outcomes in neonatal sepsis survivors treated with hAFSCs using the LPS-induced neonatal sepsis model in rats. We found that prophylactic therapy with hAFSCs improved spatial awareness and memory-based behavior in neonatal sepsis survivors at adolescence in rats. The treatment suppressed acute reactive gliosis and subsequently reduced astrogliosis in the hippocampal region over a long period of assessment. To the best of our knowledge, this is the first report that proves the concept that hAFSC treatment improves cognitive impairment in neonatal sepsis survivors. We demonstrate the efficacy of hAFSC therapy in improving the mortality and morbidity associated with neonatal sepsis.

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腹腔鏡下術後、生児を得た正所異所同時妊娠の2例

片倉慧美, 山田満稔, 池ノ上学, 田中守

日本産科婦人科内視鏡学会雑誌（(一社)日本産科婦人科内視鏡学会） 36 （ Suppl.I ） [O - 383] 2020年11月

ISSN 1884-9938

妊娠糖尿病と正常耐糖能例における胎児Fractional limb volumeの発育の比較

池ノ上学, 秋葉洋平, 遠藤豊英, 春日義史, 落合大吾, 宮越敬, 矢久保和美, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S170 - S170 2020年11月

ISSN 1346-1176

前置血管との鑑別を要した子宮頸管内静脈瘤合併妊娠の1例

遠藤豊英, 宮越敬, 玉川真澄, 長谷川慶太, 大石真希, 大谷利光, 池ノ上学, 春日義史, 落合大吾, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S406 - S406 2020年11月

ISSN 1346-1176

Placenta accreta indexによる前置癒着胎盤発症予測に関する検討

長谷川慶太, 池ノ上学, 玉川真澄, 大石真希, 遠藤豊英, 大谷利光, 春日義史, 落合大吾, 宮越敬, 田中守

超音波医学（(公社)日本超音波医学会） 47 （ Suppl. ） S374 - S374 2020年11月

ISSN 1346-1176

Survey on the use of personal protective equipment and COVID-19 testing of pregnant women in Japan

Umazume T., Miyagi E., Haruyama Y., Kobashi G., Saito S., Hayakawa S., Kawana K., Ikenoue S., Morioka I., Yamada H.

Journal of Obstetrics and Gynaecology Research （Journal of Obstetrics and Gynaecology Research） 46 （ 10 ） 1933 - 1939 2020年10月

査読有り, ISSN 13418076

Aim: To clarify the status of personal protective equipment (PPE) and coronavirus disease 2019 (COVID-19) tests for pregnant women, we conducted an urgent survey. Methods: The survey was conducted online from April 27 to May 1, 2020. Questionnaires were sent to core facilities and affiliated hospitals of the obstetrics and gynecology training program and to hospitals of the national perinatal medical liaison council. Results: A total of 296 institutions participated in our survey; however, 2 institutions were excluded. Full PPE was used by doctors in 7.1% of facilities and by midwives in 6.8%. Our study also determined that around 65.0% of facilities for doctors and 73.5% of facilities for midwives used PPE beyond the “standard gown or apron, surgical mask, goggles or face shield” during labor of asymptomatic women. N95 masks were running out of stock at 6.5% of the facilities and goggles and face shields at 2.7%. Disposable N95 masks and goggles or face shields were re-used after re-sterilization in 12% and 14% of facilities, respectively. Polymerase chain reaction (PCR) testing of asymptomatic patients was performed for 9% of vaginal deliveries, 14% of planned cesarean sections and 17% of emergency cesarean sections. The number of PCR tests for obstetrics and gynecology per a week ranged from zero to five in 92% of facilities. Conclusion: The shortage of PPE in Japan is alarming. Sufficient stockpiling of PPE is necessary to prevent unnecessary disruptions in medical care. Appropriate guidelines for PPE usage and COVID-19 testing of pregnant women at delivery are needed in Japan.

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Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan

Ochiai D., Kasuga Y., Iida M., Ikenoue S., Tanaka M.

International Journal of Gynecology and Obstetrics （International Journal of Gynecology and Obstetrics） 150 （ 2 ） 268 - 269 2020年08月

査読有り, ISSN 00207292

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Prophylactic therapy with human amniotic fluid stem cells improved survival in a rat model of lipopolysaccharide-induced neonatal sepsis through immunomodulation via aggregates with peritoneal macrophages

Sato Y., Ochiai D., Abe Y., Masuda H., Fukutake M., Ikenoue S., Kasuga Y., Shimoda M., Kanai Y., Tanaka M.

Stem Cell Research and Therapy （Stem Cell Research and Therapy） 11 （ 1 ） 300 - 300 2020年07月

査読有り

Background: Despite recent advances in neonatal care, sepsis remains a leading cause of mortality in neonates. Mesenchymal stem cells derived from various tissues, such as bone marrow, umbilical cord, and adipose tissue, have beneficial effects on adult sepsis. Although human amniotic fluid stem cells (hAFSCs) have mesenchymal stem cell properties, the efficacy of hAFSCs on neonatal sepsis is yet to be elucidated. This study aimed to investigate the therapeutic potential of hAFSCs on neonatal sepsis using a rat model of lipopolysaccharide (LPS)-induced sepsis. Methods: hAFSCs were isolated as CD117-positive cells from human amniotic fluid. Three-day-old rat pups were intraperitoneally treated with LPS to mimic neonatal sepsis. hAFSCs were administered either 3 h before or at 0, 3, or 24 h after LPS exposure. Serum inflammatory cytokine levels, gene expression profiles from spleens, and multiple organ damage were analyzed. hAFSC localization was determined in vivo. In vitro LPS stimulation tests were performed using neonatal rat peritoneal macrophages co-cultured with hAFSCs in a cell-cell contact-dependent/independent manner. Immunoregulation in the spleen was determined using a DNA microarray analysis. Results: Prophylactic therapy with hAFSCs improved survival in the LPS-treated rats while the hAFSCs transplantation after LPS exposure did not elicit a therapeutic response. Therefore, hAFSC pretreatment was used for all subsequent studies. Inflammatory cytokine levels were elevated after LPS injection, which was attenuated by hAFSC pretreatment. Subsequently, inflammation-induced damages in the brain, lungs, and liver were ameliorated. hAFSCs aggregated with peritoneal macrophages and/or transiently accumulated in the liver, mesentery, and peritoneum. Paracrine factors released by hAFSCs induced M1-M2 macrophage polarization in a cell-cell contact-independent manner. Direct contact between hAFSCs and peritoneal macrophages further enhanced the polarization. Microarray analysis of the spleen showed that hAFSC pretreatment reduced the expression of genes involved in apoptosis and inflammation and subsequently suppressed toll-like receptor 4 signaling pathways. Conclusions: Prophylactic therapy with hAFSCs improved survival in a rat model of LPS-induced neonatal sepsis. These effects might be mediated by a phenotypic switch from M1 to M2 in peritoneal macrophages, triggered by hAFSCs in a cell-cell contact-dependent/independent manner and the subsequent immunomodulation of the spleen.

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