京都大学 大学院医学研究科 人間健康科学系専攻 病理学研究室（形態形成医療科学）

金橋くんの修士論文がAnat Recに掲載されました。おめでとうございます。

肝臓の立体化、定量（廣瀬さん）、肝臓の形態異常個体のスクリーニング（田中さん）の研究、高解像度のMRI、位相CTの撮像と、多くの協力と成果のおかげで、論文にすることができました。

• 1156例（CS14-23）のMRI画像から、肝臓形成異常例をスクリーニング
• 高解像度の位相コントラストX線CT(PCT)で胚子内部の詳細な解析
• 極小肝臓グループの異常は、肝無形成（2例）、肝低形成（4）、および肝葉欠損（1）
• これらは、肝造血障害により子宮内胎児死亡につながる可能性
• 外部正常胚の子宮内集団における CS18 -21 の肝形成不全の有病率は、約 1.7%

18.Kanahashi T, Yamada S, Tanaka M, Hirose A, Uwabe C, Kose K, Yoneyama A, Takeda T, Takakuwa T, A novel strategy to reveal the latent abnormalities in human embryonic stages from a large embryo collection, Anatomical Record, 299,8-24,2016  10.1002/ar.23281(概要), *299(1),2016の表紙に採用されました。DOI: 10.1002/ar.23206 (cover page)

金橋くんの修士論文の概要>>

ABSTRACT

The cause of spontaneous abortion of normal conceptuses remains unknown in most cases. The study was aimed to reveal the latent abnormalities by using a large collection of embryo images from a magnetic resonance imaging (MRI) database and novel phase-contrast radiographic computed tomography (PXCT). MRI from 1,156 embryos between Carnegie stage (CS) 14 and CS23 from the Kyoto Collection were screened by using the volume of the liver as the target organ. Embryos with liver volumes ≥2 SD above or below the mean for the stage of development were screened and examined precisely on MRI. Embryos with potentially abnormal livers were further analyzed by using PXCT. Liver abnormality was detected in all 7 embryos in the extra-small liver group and in 2 of 8 embryos in the extra-large liver group. The abnormalities in the extra-small liver group consisted of hepatic agenesis (2 embryos), hepatic hypogenesis (4), and liver lobe defect (1). Among the 7 extra-small liver group, 2 had only liver abnormalities and 5 exhibited complications in other organs. Of the 2 embryos in the extra-large liver group, one had only a single liver abnormality and the other had a morphologically abnormal liver with complications in other organs. Most of such liver abnormality cases are not survive, as liver function becomes essential. The prevalence of liver malformations in CS18 and CS21 in the intrauterine population of externally normal embryos is approximately 1.7%. The present study is the first step toward the elucidation of the latent abnormalities resulting in spontaneous abortion in externally normal embryos. Anat Rec, 299:8–24, 2016.

中島君、片山さん、白石くんの3人の学生や、多くのOffice Assistantの協力を得て、6年かけて解析した論文「ヒト胚子期における脳形態形成」がNeuroimageに受諾されました。また、SupplyのビデオはData in Briefに、3D元データの一部はMorphoMに掲載されました。

• ヒト胚子期の脳の三次元形成を提示
• 脳の容積は、CS 13 – 23 間で 164.4 倍に増加
• 胚全体に対する脳実質の体積の比率は、CS15-23の間でほぼ一定（11.6〜15.5％）
• 分化成長にともなう脳組織の不均一な厚さを 3D で視覚化
• 結果は、胚子期の脳の発生を定量化し評価する基準値になりうる可能性

13. Shiraishi N, Katayama A, Nakashima T, Yamada S, Uwabe C, Kose K, Takakuwa T, Morphology and morphometry of the human embryonic brain: A three-dimensional analysis, NeuroImage, 2015, 115, 96-103, 10.1016/j.neuroimage.2015.04.044, (概要), [OpenAccess]

12. Shiraishi N, Katayama A, Nakashima T, Yamada S, Uwabe C, Kose K, Takakuwa T, Three-dimensional morphology of the human embryonic brain, Data in Brief, 2015, 4, 116-118, 10.1016/j.dib.2015.05.001 [OpenAccess]

15. Shiraishi N, Katayama A, Nakashima T, Shiraki N, Yamada S, Uwabe C, Kose K, Takakuwa T, 3D model related to the publication: Morphology of the human embryonic brain and ventricles,  MorphoMuseuM 1 (3)-e3. doi: 10.18563/m3.1.3.e3. [OpenAccess]

Abstract

The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing Amira™ software. The brain volume, excluding the ventricles (brain tissue), was 1.15 ± 0.43 mm³ (mean ± SD) at CS13 and increased exponentially to 189.10 ± 36.91 mm³ at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26 ± 0.15 mm³ at CS13. The volume increased exponentially until CS23, when it reached 110.99 ± 27.58 mm³. The mean volumes of the mesencephalon and rhombencephalon were 0.20 ± 0.07 mm³ and 0.69 ± 0.23 mm³ at CS13, respectively; the volumes reached 21.86 ± 3.30 mm³ and 56.45 ± 7.64 mm³ at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6–15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development.

Highlights

Three-dimensional morphogenesis of the human embryonic brain was presented from MRI.•

The volume of three brain vesicles and ventricles were measured at 101 embryos.•

The brain volume exponentially increased 164.4-fold from Carnegie stage 13 to 23.•

The volume ratio of the brain to whole embryo remained nearly constant.•

The non-uniform thickness of the brain tissue during development was 3D visualized.

竹谷さんの卒業論文が、 Congenital Anomalies 55巻(2015)に掲載されました。

本論文の内容は第104回日本病理学会総会で発表しました。

• 妊娠中期 (16-25週) ヒト胎児の側脳室の形成を解析
• 16週の；側脳室の前角、中心部、後角、下角の主要4領域が区分可能。
• 側脳室は近接する大脳の外方、内方への成長の影響を受け、主に伸長と狭小化という変化を示す。
• 6個のパラメータ (総前後長、前後角間長、後角長、中心部の厚さ、総側脳室高、下角間長) と頭蓋横径(BPD)との関連性をsimple regression analysisを用いて検討
• BPDと関連性の高い計測値は、総前後長、前後角間長、後角長、中心部の厚さ（R2=0.80-0.93)
• 総側脳室高、下角間長は中等度 (R2=0.56-0.73)
• BPDと側脳室体積とは関連性がない(R2=0.13).
• 脳室の計測は、胎内での胎児脳の健全な成長と発生を評価する標準的手法を確立するのに寄与する可能性あり

Taketani K, Yamada S, Uwabe C, Okada T, Togash K, Takakuwa T, Morphological features and length measurements of fetal lateral ventricles at 16–25 weeks of gestation by magnetic resonance imaging, Congenit Anom (Kyoto), 2015, 55, 99-102. doi: 10.1111/cga.12076

Abstract

Normal growth of the lateral ventricles (LVs) was characterized three-dimensionally using magnetic resonance imaging (MRI) data from 16 human fetuses at 16–25 weeks of gestation. The LV was differentiated into four primary regions, the anterior horn, central parts, posterior horn, and inferior horn, at 16 weeks of gestation. The LV changed shape mainly by elongation and narrowing, which corresponded to the external and internal growth of the surrounding cerebrum. Six length parameters measured in the LV correlated with biparietal diameter by simple regression analysis (R² range, 0.56–0.93), which may be valuable for establishing a standardized prenatal protocol to assess fetal well-being and development across intrauterine periods. No correlation was found between biparietal diameter and LV volume (R² = 0.13).

海外君、名古さんの論文で作成した胃の立体像が解剖学雑誌Anatomical Record 297巻5号の表紙に採用されるとともに、ビデオを結果として示すことのできるAR WOW-Video Articleの第1号の論文として採用されました。

8. Morphogenesis and Three-Dimensional Movement of the Stomach During the Human Embryonic Period (page C1)

N. Kaigai, A. Nako, S. Yamada, C. Uwabe, K. Kose and T. Takakuwa

Anat RecはAmerican Association of Anatomists (AAA)の公認雑誌で、100年以上の発行歴のある由緒ある雑誌です。永く世界の医学、解剖学、発生学の分野を牽引してきました。本雑誌は、さらに、最近のe-Page技術を取り入れたWOWという雑誌を本号から採用しました。これは、ビデオが論文の結果として重要な役割を果たす際にそのビデオが永久に保存できるようにしたものです。その第１号の論文として、海外君の胃の形態形成と動きについての論文が選ばれました。

Editorialでは、”Human Embryos are Turning on the e-Pages of AR”（ヒト胚子がARのe-Pageに灯をともす…）という題で,　インタビューを受け、私たちの予想以上に讃えていただきました。(Anat Rec  297(5) ; 799–801, 2014)

Our rationale for imaging the human stomach during development.

“All of the authors are well-versed with the fact that the stomach develops as the local widening of the foregut at Carnegie Stage (CS) 13, as well as the morphology and position of the stomach in adults. But what are the developmental dynamics from the former to the latter? While I (Dr. Takakuwa) was a university student, I read a textbook that explained that the developmental dynamics of the stomach follow the order of linear movement along the caudal direction, rotation around the longitudinal (Z) axis, and rotation around the dorsoventral (X) axis. This explanation aroused my curiosity with regard to the position of the abdominal organs around the stomach, such as the esophagus, pancreas, and duodenum, which are restricted in their positions after CS17. For example, around CS20, movement of the stomach is restricted at both its entrance (cardia) and the exit (pyloric antrum) near the mid-sagittal plane.

We designed our study to sort out the dynamic process that places the stomach in its definitive position in the abdomen. Accordingly, we analyzed the external morphology and morphometry of the human embryonic stomach, as well as documented its precise 3D movements, using magnetic resonance (MR) imaging data of human embryos in the “Kyoto Collection”. We discovered that the line connecting the cardia and the pyloric antrum of the stomach does not rotate around the dorsoventral (X) axis, as widely believed, but rotates around the transverse (Y) axis. The stomach “appears” to move towards the left, laterally and caudally, as deflection and differential growth progresses. We found that the developmental morphology of the three-dimensionally reconstructed stomach was not “analogous” to that of adults or as described in recent textbooks. Rather, we found that the stomach’s developmental morphology is as documented in a study a century before (Lewis 1912), in which the stomach was precisely hand drawn by a special artist [note added by Editor: Lewis studied the stomachs of five human embryos that were 10 mm and 45 mm in length; Harvard Embryological Collection, Series 1000]. We are gratified that our MR imaging data of embryos enhance the value of the Kyoto Collection, not only as archives of historical specimens but also as useful research resources for the future.”

Contributed by Kaigai and colleagues, Kyoto University, Graduate School of Medicine.