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山崎さんの修士論文がCells Tissues Organsに掲載

山崎さんの修士論文がCells Tissues Organsに受諾されました。

気管軟骨、喉頭軟骨の形態形成について軟骨の発生段階を立体的に細かく示しました。頭尾方向の分化の同調性については、これまでの報告と異なっています。

  • Phase 2の最初の分化 は正中面ではなく、舌骨、甲状軟骨、輪状軟骨、気管軟骨ともに両外側に 一つずつあり、それぞれのタイムラインに従って分化し正中面で融合した。
  • 気管軟骨のPhase2 の分化は頭側で始まり、体軸に沿って短期間で伝播し、Phase 3 の分化が始まる前に同調する。
  • Phase 3 分化は正中で始まり、側方に伝播する。頭尾方向については、同調して分化し、差はない。
  • 気管気管支軟骨の数と分布は成人と同様である。
CS20 気管の縦断面;気管軟骨は頭尾方向でPhase 2の分化を示しており、同調している。

54. Yamazaki Y, Kanahashi T, Yamada S, Männer J, Takakuwa T. Three-dimensional analysis of human laryngeal and tracheobronchial cartilages during the late embryonic and early fetal period. Cells Tissues Organs, 2021 in press

Abstract

Laryngeal and tracheobronchial cartilages are present as unique U-shaped forms around the respiratory tract and contribute to the formation of rigid structures required for the airway. Certain discrepancies still exist concerning cartilage formation in humans. To visualize the accurate timeline of cartilage formation, tracheobronchial and laryngeal cartilages were 3D reconstructed based on serial tissue sections during the embryonic period (Carnegie stage [CS] 18–23) and early fetal period (crown rump length [CRL] = 35–45 mm). The developmental phases of the cartilage were estimated by histological studies, which were performed on the reconstructed tissue sections. The hyoid greater horns were recognizable at CS18 (phase 2). Fusion of 2 chondrification centers in the mid-sagittal region was observed at CS19 in the hyoid bone, at CS20 in the cricoid cartilage, and in the specimen with CRL 39 mm in the thyroid cartilage. Phase 3 differentiation was observed at the median part of the hyoid body at CS19, which was the earliest among all other laryngeal and tracheobronchial cartilages. Most of the laryngeal cartilages were in phase 3 differentiation at CS22 and in phase 4 differentiation at CS23. The U-shaped tracheobronchial cartilages with phase 2 differentiation covered the entire extrapulmonary region at CS20. Phase 3 differentiation started on the median section and propagates laterally at CS21. The tracheobronchial cartilages may form simultaneously during the embryonic period at CS22-23 and early fetal periods, similar to adults in number and distribution. The spatial propagation of the tracheal cartilage differentiation provided in the present study indicates that cartilage differentiation may have propagated differently on phase 2 and phase 3. This study demonstrates a comprehensible timeline of cartilage formation. Such detailed information of the timeline of cartilage formation would be useful to improve our understanding of the development and pathophysiology of congenital airway anomalies.

寺島さんの修士論文がJ Anatに掲載

胚子期末大脳におけるプレサブプレートの3次元分布

寺島さんの修士論文がJ Anatomyに受諾されました。おめでとうございます。

  • 胎児期のみに出現し、大脳皮質の形成、自発活動の開始に関わる可能性のあるプレサブプレート(pSP)の形成について、連続組織画像を用いて立体的に視覚化し、定量化した。
  • PSPはCS21で大脳壁の中外側領域に存在し、この領域を中心とした拡大が観察され、胎児期の初期(CRL 39 mm)に大脳半球全体で観察した。
  • pSP-IZ の厚さは 3D で表示され、中外側領域で大きかった。CRL 64 mm)に、厚い領域は、島の原基の周りの外側、上部、および後部領域に拡大しました。
  • 層構造は、発達初期に厚くなるのではなく、薄く成長して広がった。

Terashima, M., Ishikawa A., Männer J., Yamada S.&Takakuwa T. (2021) Early development of the cortical layers in the human brain. Journal of Anatomy, 239, 1039–1049. https://doi.org/10.1111/joa.13488

Abstract

The cortical plate (CP) first appears at seven postconceptional weeks (pcw), when it splits the preexisting preplate into two layers, the marginal zone and the presubplate (pSP). Although three-dimensional (3D) analysis using fetal magnetic resonance imaging and two-dimensional tissue observations have been reported, there have been no studies analyzing the early development of the layer structure corresponding to the pSP stage in 3D. Here, we reconstructed 3-D models of the brain with a focus on the cortical layers in pSP stage. To achieve this, we digitized serial tissue sections of embryos between CS20 and CS23 from the Kyoto Collection (n = 7, approximately 7–8.5 pcw), and specimens at early fetal phase from the Blechschmidt Collection (n = 2, approximately 9.5–12 pcw, crown rump length [CRL] 39 and 64 mm). We observed tissue sections and 3D images and performed quantitative analysis of the thickness, surface area, and volume. Because the boundary between pSP and the intermediate zone (IZ) could not be distinguished in hematoxylin and eosin-stained sections, the two layers were analyzed together as a single layer in this study. The histology of the layers was observed from CS21 and became distinct at CS22. Subsequently, we observed the 3-D models; pSP-IZ was present in a midlateral region of the cerebral wall at CS21, and an expansion centered around this region was observed after CS22. We observed it over the entire cerebral hemisphere at early fetal phase (CRL 39 mm). The thickness of pSP-IZ was visible in 3D and was greater in the midlateral region. At the end of the pSP stage (CRL 64 mm), the thick region expanded to lateral, superior, and posterior regions around the primordium of the insula. While, the region near the basal ganglia was not included in the thickest 10% of the pSP-IZ area. Middle cerebral artery was found in the midlateral region of the cerebral wall, near the area where pSP-IZ was observed. Feature of layer structure growth was revealed by quantitative assessment as thickness, surface area, and volume. The maximum thickness value of pSP-IZ and CP increased significantly according to CRL, whereas the median value increased slightly. The layer structure appeared to grow and spread thin, rather than thickening during early development, which is characteristic during pSP stages. The surface area of the cerebral total tissue, CP, and pSP-IZ increased in proportion to the square of CRL. The surface area of CP and pSP-IZ approached that of the total tissue at the end of the pSP stage. Volume of each layer increased in proportion to the cube of CRL. pSP-IZ and CP constituted over 50% of the total tissue in volume at the end of the pSP stages. We could visualize the growth of pSP-IZ in 3D and quantify it during pSP stage. Our approach allowed us to observe the process of rapid expansion of pSP-IZ from the midlateral regions of the cerebral wall, which subsequently becomes the insula.

ヒト胎児期初期の脳の形態形成についての論文がJ Anatに掲載されました

ヒト胎児期初期の脳の形態形成についての論文がJ Anatomyに掲載されました。5年以上かけて、ようやくまとめることができました。

  • 高解像度MRIを用いて胎児期初期の(受胎後 9 ~ 13 週) の脳の形態計測学的分析を行った。
  • 脳梁の出現(CRL62mm), 皮質内側の脳溝の出現(CRL114mm),
  • 小脳半球、後外側裂溝、小脳半分の結合、虫部の形成(CRL43.5mm), 一次裂溝の出(CRL56mm), 錐体前裂(CRL75mm), 
  • 大脳側面における大脳の比率 (長さ/高さ) と基準線に対する大脳の角度は、大脳の成長と C 字型の形成を反映している可能性がある。
  • これらの所見は、胎児期初期を細分化するための候補となる可能性がある。

52. Takakuwa T, Shiraishi N, Terashima M,Yamanaka M, Okamoto I, Imai H, Ishizu K, Yamada S, Ishikawa A, Kanahashi T. Morphology and morphometry of the human early fetal brain: A three-dimensional analysis. J Anatomy; 239 (2) 498-516, 2021, doi.org/10.1111/joa.13433

Abstract

Morphometric analyses in the early foetal phase (9-13 postconceptional week) are critical for evaluating normal brain growth. In this study, we assessed sequential morphological and morphometric changes in the foetal brain during this period using high-resolution T1-weighted magnetic resonance imaging (MRI) scans from 21 samples preserved at Kyoto University. MRI sectional views (coronal, mid-sagittal, and horizontal sections) and 3D reconstructions of the whole brain revealed sequential changes in its external morphology and internal structures. The cerebrum’s gross external view, lateral ventricle and choroid plexus, cerebral wall, basal ganglia and thalamus, and corpus callosum were assessed. The development of the cerebral cortex, white matter microstructure, and basal ganglia can be well-characterized using MRI scans. The insula became apparent and deeply impressed as brain growth progressed. A thick, densely packed cellular ventricular/subventricular zone and ganglionic eminence became apparent at high signal intensity. We detected the emergence of important landmarks which may be candidates in the subdivision processes during the early foetal period; the corpus callosum was first detected in the sample with crown-rump length (CRL) 62 mm. A primary sulcus on the medial part of the cortex (cingulate sulcus) was observed in the sample with CRL 114 mm. In the cerebellum, the hemispheres, posterolateral fissure, union of the cerebellar halves, and definition of the vermis were observed in the sample with CRL 43.5 mm, alongside the appearance of a primary fissure in the sample with CRL 56 mm and the prepyramidal fissure in the sample with CRL 75 mm. The volumetric, linear, and angle measurements revealed the comprehensive and regional development, growth, and differentiation of brain structures during the early foetal phase. The early foetal period was neither morphologically nor morphometrically uniform. The cerebral proportion (length/height) and the angle of cerebrum to the standard line at the lateral view of the cerebrum, which may reflect the growth and C-shape formation of the cerebrum, may be a candidate for subdividing the early foetal period. Future precise analyses must establish a staging system for the brain during the early foetal period. This study provides insights into brain structure, allowing for a correlation with functional maturation and facilitating the early detection of brain damage and abnormal development.

北沢さんの修士論文がJ Anatに掲載されました

糸球体結合と尿路樹の分岐との関連性を示すモデル

北沢さんの修論がJ Anatomyに受諾されました。

ヒト腎臓の尿路樹と腎小体には下記のような不可思議なことが知られています。

  • 腎小体は尿路樹の末梢枝のみに結合する
  • 尿路樹の枝数は分岐次数が増えても2nで増加しない

これを説明するモデルはいくつか提唱されていましたが、決着していませんでした。

私達はヒト胚子期の腎臓の形成を、尿路樹形成と糸球体形成との相互関係に着目し定量的に詳細に検討しました。得られたデータを合理的に説明できる以下の様なモデルを提唱しました

  • 糸球体はCS19に初めて出現、尿路樹への結合がみられる。
  • 糸球体の結合した尿路樹の末端の枝 は、先端でさらに先端分岐することはない
  • 糸球体の結合した尿路樹の末端の枝 は、結合部位より基部側での分岐 (側方分岐) が継続する

同モデルは、これまで提唱されていた3つのモデルのうちの3番目を支持するものです。

<修士論文の概要>

Kitazawa H, Fujii S, Ishiyama H, Matsubayashi J, Ishikawa A, Yamada S, Takakuwa T. Nascent nephrons during human embryonic development: Spatial distribution and relationship with urinary collecting system. J Anatomy 2021; 238, 455-466, in press.DOI: 10.1111/JOA.13308

腎小体は尿路樹の末梢枝のみに結合するという観察を説明するモデル
Abstract

The two major components of the metanephros, the urinary collecting system (UCS) and nephron, have different developmental courses. Nephron numbers vary widely between species and individuals and are determined during fetal development. Furthermore, the development of nascent nephrons may contribute to the expansion of the proximal part of the UCS. This study investigated the distribution of nascent nephrons and their interrelationship with UCS branches during human embryogenesis. We obtained samples from 31 human embryos between Carnegie stages (CSs) 19 and 23 from the Kyoto Collection at the Congenital Anomaly Research Center of Kyoto University in Japan. Serial histological sections of the metanephros with the UCS were digitalized and computationally reconstructed for morphological and quantitative analyses. The three-dimensional (3D) coordinates for the positions of all UCS branch points, end points, attachment points to nascent nephrons (APs), and renal corpuscles (RCs) were recorded and related to the developmental phase. Phases were categorized from phase 1 to phase 5 according to the histological analysis. The UCS branching continued until RCs first appeared (at CS19). End branches with attached nascent nephrons (EB-AP[+]) were observed after CS19 during the fifth generation or higher during the embryonic period. The range of end branch and EB-AP(+) generation numbers was broad, and the number of RCs increased with the embryonic stage, reaching 273.8 ± 104.2 at CS23. The number of RCs connected to the UCS exceeded the number not connected to the UCS by CS23. The 3D reconstructions revealed RCs to be distributed around end branches, close to the surface of the metanephros. The RCs connected to the UCS were located away from the surface. The APs remained near the end point, whereas connecting ducts that become renal tubules were found to elongate with maturation of the RCs. Nascent nephrons in RC phases 3-5 were preferentially attached to the end branches at CS22 and CS23. The mean generation number of EB-AP(−) was higher than that of EB-AP(+) in 19 of 22 metanephros and was statistically significant for eight metanephros at CS22 and CS23. The ratio of the deviated branching pattern was almost constant (29%). The ratio of the even branching pattern with EB-AP(+) and EB-AP(+) to the total even branching pattern increased with CS (9.2% at CS21, 19.2% at CS22, and 45.4% at CS23). Our data suggest the following: EB-AP(+) may not branch further at the tip (i.e., by tip splitting), but branching beneath the AP (lateral branching) continues throughout the embryonic stages. Our study provides valuable data that can further the understanding of the interactions between the UCS and nascent nephrons during human embryogenesis.

藤井さんの研究がPLoS One に掲載

藤井さんの研究がPLoS One に受諾されました。

ヒトの気管支の分岐様式についてmonopodial(側方分岐)か dipodial(先端分岐)かについて、気管支の枝の長さを基本に解析し以下のことを見出した

  • 中枢部の25気管支(葉気管支、区域気管支、亜区域気管支)形成は左上葉気管支から分岐する舌状気管支を除いて側方分岐による
  • 葉気管支と区域気管支の分岐様式は、マウスの肺とヒトの肺で類似しているが、亜区域気管支においては異なっている
  • 胚子期に気管支短縮などのリモデリングはみられない

Fujii S, Muranaka T, Matsubayashi J, Yamada S, Yoneyama A, Takakuwa T. Bronchial tree of the human embryo: categorization of the branching mode as monopodial and dipodial, PLoS One 2021, Published: January 15, 2021, https://doi.org/10.1371/journal.pone.0245558

Abstract

Some human organs are composed of bifurcated structures. Two simple branching modes—monopodial and dipodial—have been proposed. With monopodial branching, child branches extend from the sidewall of the parent branch. With dipodial branching, the tip of the bronchus bifurcates. However, the branching modes of the human bronchial tree have not been elucidated precisely. A total of 48 samples between Carnegie stage (CS) 15 and CS23 belonging to the Kyoto Collection were used to acquire imaging data with phase-contrast X-ray computed tomography. Bronchial trees of all samples were three-dimensionally reconstructed from the image data. We analyzed the lobar bronchus, segmental bronchus, and subsegmental bronchus. After calculating each bronchus length, we categorized the branching mode of the analyzed bronchi based on whether the parent bronchus was divided after generation of the analyzed bronchi. All lobar bronchi were formed with monopodial branching. Twenty-five bifurcations were analyzed to categorize the branching mode of the segmental and subsegmental bronchi; 22 bifurcations were categorized as monopodial branching, two bifurcations were not categorized as any branching pattern, and the only lingular bronchus that bifurcated from the left superior lobar bronchus was categorized as dipodial branching. The left superior lobar bronchus did not shorten during the period from CS17 or CS18, when the child branch was generated, to CS23. All analyzed bronchi that could be categorized, except for one, were categorized as monopodial branching. The branching modes of the lobar bronchus and segmental bronchus were similar in the mouse lung and human lung; however, the modes of the subsegmental bronchi were different. Furthermore, remodeling, such as shrinkage of the bronchus, was not observed during the analysis period. Our three-dimensional reconstructions allowed precise calculation of the bronchus length, thereby improving the knowledge of branching morphogenesis in the human embryonic lung.

季さんの論文がAnatomical Recに掲載

季さんの論文がAnat Recに掲載されました。

腹壁(腹直筋:緑)と臍帯(赤丸)(CRL57mm)

胎児期初期の臍帯ヘルニアの還納と腹壁(腹直筋)の形成との関連性について検討しました。

  • 成長とともに腹直筋の走行は、腹壁の外側部分から正中線領域にシフトした。
  • 腹直筋の尾側部分はほとんど標本で菲薄であった.
  • 腹直筋の長さ、腹囲は、胎児の成長と正の相関を示した。
  • ダイナミックな腸管の再配置にもかかわらず、腹直筋、腹直筋間の距離、臍帯サイズはほとんど変化しない。
  • 腹直筋を含む腹壁の形成は、臍帯体腔内または腹腔内の中腸 ヘルニアの段階とは無関係

Ji X, Ishikawa A, Nagata A, Yamada S, Imai H, Matsuda T, Takakuwa T, Relationship between rectal abdominis muscle position and physiological umbilical herniation and return: a morphological and morphometric study. Anat Rec 2020, 303, 12, 3044-3051. doi: 10.1002/ar.24486

受諾は1年前だったのですが、ようやくpublishされました。

Abstract

The herniation of the intestinal loop (IL) in the extraembryonic coelom and its return to abdominal cavity is in parallel with the formation of the rectal abdominis muscle (RAM). Using high-resolution magnetic resonance imaging data of human fetuses (n = 19, CRL22-69 mm; stored at Kyoto Collection), this study aimed to analyze the relationship between the development of RAM and phase of IL herniation. The RAM runs at the lateral part of the abdominal wall in the small samples in the herniation phase. The position was shifted to the midline area in the larger samples in the herniation phase. According to fetal growth, the caudal ends of the muscles extended along the umbilical ring towards the pubis, though the caudal part of the RAMs were thin and faint in most of the samples. Length measurements related with the growth of the abdominal wall including RAM and abdominal circumference showed positive correlation with fetal growth. On the contrary, diastasis of RAMs and the width and area of the umbilical ring were almost constant according to fetal growth. Such morphometric value showed no obvious changes regardless of the phases of herniation. The ratio of the width and diastasis of the RAMs to the circumference was decreased, indicating that the closure of the ventral body wall was influenced by growth differences. The present data indicate that the formation of the abdominal wall including RAM is independent of the phase of IL herniation, whether in the extraembryonic coelom or in the abdominal cavity.

西谷さん、鳥居さんの胎児心臓の解析がJAHAに掲載

西谷さんの修士論文、鳥居さんの卒業論文;胎児心臓のDT-MRIによる解析がJAHAに掲載されました。

  • 従来の報告より8週以上若い時期のヒトの心筋走行を高解像度DT-MRIデータを用いて検出しました。
  • ヒトの心筋の走行の配置、螺旋状の角度等は、成人とすでに同様であることから、心筋構築の青写真は胚子期末(CS20-23, GSA8W)には、すでに形成されていることをから明らかにしました。
  • データは古典的な心筋バンド説(心筋はひとつながりのバンド状のものが立体的に折り畳まれて形成されている)を否定しました。

本研究成果は、京都大学HP(トピックス)でも紹介されました。

ヒト胎児心臓の心筋線維方向を追跡 -受精後8週の心筋線維は成人と同じ配列をする-  外部リンク[京都大学HP(トピックス)]

2020/10/13 医療NEWSにて,ヒト胎児の心臓、受精後8週で心筋線維の配列が成人と同様であることが判明-京大ほか が紹介されました.

46. Nishitani S, Torii N, Imai H, Haraguchi R, Yamada S, Takakuwa T, Development of helical myofiber tracts in the human fetal heart: Analysis of myocardial fiber formation in the left ventricle from the late human embryonic period using diffusion tensor magnetic resonance imaging. Journal of the American Heart Association, 2020, 19(9) doi:10.1161/JAHA.120.016422

Abstract

Background

Detection of the fiber orientation pattern of the myocardium using diffusion tensor magnetic resonance imaging lags ≈12 weeks of gestational age (WGA) behind fetal myocardial remodeling with invasion by the developing coronary vasculature (8 WGA). We aimed to use diffusion tensor magnetic resonance imaging tractography to characterize the evolution of fiber architecture in the developing human heart from the later embryonic period.

Methods and Results

Twenty human specimens (8–24 WGA) from the Kyoto Collection of Human Embryos and Fetuses, including specimens from the embryonic period (Carnegie stages 20–23), were used. Diffusion tensor magnetic resonance imaging data were acquired with a 7T magnetic resonance system. Fractional anisotropy and helix angle were calculated using standard definitions. In all samples, the fibers ran helically in an organized pattern in both the left and right ventricles. A smooth transmural change in helix angle values (from positive to negative) was detected in all 16 directions of the ventricles. This feature was observed in almost all small (Carnegie stage 23) and large samples. A higher fractional anisotropy value was detected at the outer side of the anterior wall and septum at Carnegie stage 20 to 22, which spread around the ventricular wall at Carnegie stage 23 and in the early fetal samples (11–12 WGA). The fractional anisotropy value of the left ventricular walls decreased in samples with ≥13 WGA, which remained low (≈0.09) in larger samples.

Conclusions

From the human late embryonic period (from 8 WGA), the helix angle arrangement of the myocardium is comparable to that of the adult, indicating that the myocardial structure blueprint, organization, and integrity are already formed.

田中さん、坂本さんの卒業研究がPLoS ONEに掲載

田中さん、坂本さんの卒業研究がPLoS ONEに掲載されました。胎児期の上肢帯の形態形成、位置の変化について詳述しました。

  • CS18で、烏口骨と上腕骨頭とともに肩甲骨体部を最初に検出
  • 肩甲骨下角は尾側方向に拡大したが、頭側はほとんど位置をかえない
  • 肩甲骨は胎児期には独特な位置(椎体の前方から側方への移動)、向き( 内部、上方回転)を示す

46. Tanaka S, Sakamoto R, Kanahashi T, Yamada S, Imai H, Yoneyama A, Takakuwa T. Shoulder girdle formation and positioning during embryonic and early fetal human development. PLoS ONE 2020, 15(9): e0238225. https://doi.org/10.1371/journal.pone.0238225

Abstract

Positional information on the shoulder girdle (the clavicle and scapula) is important for a better understanding of the function of the upper limb in the locomotive system as well as its associated disease pathogenesis. However, such data are limited except for information on the axial position of the scapula. Here, we describe a three-dimensional reconstruction of the shoulder girdle including the clavicle and scapula, and its relationship to different landmarks in the body. Thirty-six human fetal specimens (crown-rump length range: 7.6–225 mm) from the Kyoto Collection were used for this study. The morphogenesis and three-dimensional position of the shoulder girdle were analyzed with phase-contrast X-ray computed tomography and magnetic resonance imaging. We first detected the scapula body along with the coracoid and humeral head at Carnegie stage 18; however, the connection between the body and coracoid was not confirmed at this stage. During development, all landmarks on the shoulder girdle remained at the same axial position except for the inferior angle, which implies that the scapula enlarged in the caudal direction and reached the adult axial position in the fetal period. The scapula body was rotated internally and in the upward direction at the initiation of morphogenesis, but in the fetal period the scapula body was different than that in the adult position. The shoulder girdle was located at the ventral side of the vertebrae at the time of initial morphogenesis, but changed its position to the lateral side of the vertebrae in the late embryonic and fetal periods. Such a unique position of the shoulder girdle may contribute to the stage-specific posture of the upper limb. Adequate internal and upward rotation of the scapula could help in reducing the shoulder width, thereby facilitating childbirth. The data presented in this study can be used as normal morphometric references for shoulder girdle evaluations in the embryonic and fetal periods.