胚胎發育及幹細胞
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(2) Outline 1. 2. 3. 4. 5.. 胚胎學 (embryology) vs. 發育生物學 (developmental biology) 模式生物 (model organisms) 動物發育的主要階段 發育過程之機制 組織再生與幹細胞. 胚胎學 (Embryology) : The development of an embryo from the fertilized egg 發育生物學 (Developmental Biology) is to understand how multicellular organism develop. 2.
(3) 何謂發育生物學？ A Body-Building Plan ‧發育生物學(developmental biology) 源自於胚胎學(embryology) ‧胚胎學：探討受精卵到出生的過程. ‧發育生物學包含： 胚胎學 + 個體生長、器官及組織受損的修復與再 生、 老化、疾病的發生與治療等. 胚胎學上古老的爭論 Preformation theory (先成說). Epigenesis theory (漸成說). 胚胎的各部份是一開始就存在? 還是在發育過程中逐漸形成的？. 3.
(4) 顯微鏡的發明 細胞學說的確立 基因概念的形成 胚胎發育符合漸成說的理論. 發育的觀念: A Life cycle of Frog. 4.
(5) 發育的三要素: 1. 生長/分裂 growth/cleavage Increase in cell number Increase in cell size. 2. 分化 Differentiation The fate of daughter cells. 3. 形態發生 Morphogenesis The formation of shapes and patterns. 發育的中心主題: 細胞如何分化成特定種類？ 細胞如何移動到特定位置？ 如何控制這些細胞發育成為不同類型的細胞組 織？ 細胞如何分化成特定種類？. 5.
(6) What happen if genetic control goes wrong in limb development?. 發育出問題, 有些會遺傳, 因為基因控制發育. 模式生物 – nematode (Caenorhabditis elegans) – fruit fly (Drosophila melanogaster ) – sea urchins – South African Frog (Xenopus laevis) – Zebrafish (Danio Renio) – chick – mouse – plant (Arabidopsis thaliana) 用以研究發育生物學, 人類疾病. 6.
(7) 人類不利於作發育, 疾病模式之原因： ‧ 1.壽命長。 ‧ 2.再生時間緩慢。 ‧ 3.子代少。 ‧ 4.極度異質性。 ‧ 5.無法長期控制飼養方式及社經生活。 ‧ 6.定量資料如飲食、飼養方面缺乏。 ‧ 7.道德上的問題。. 錯誤的觀念／有關實驗動物模式 ‧ 1.動物是人類的迷你種。 ‧ 2.動物模式是人類疾病的精確複製品。 ‧ 3.在演化上居較高等級之動物，越能預測人類疾病。 ‧ 4.囓齒類太小，不適合於大多數研究。 ‧ 5.發現一個人類疾病動物模式相等於對人類疾病的了解有重大進展。. nematode (Caenorhabditis elegans). 7.
(8) Time after fertilization (hours). Fig. 47-22 Zygote. 0. First cell division. Nervous system, outer skin, musculature. 10. Outer skin, nervous system. Musculature, gonads. Germ line (future gametes). Musculature. Hatching. Intestine Intestine Mouth. Anus Eggs. Vulva. ANTERIOR. POSTERIOR 1.2 mm. fruit fly (Drosophila melanogaster ). 8.
(9) Adult fruit fly. Fruit fly embryo (10 hours). Fly chromosome. Homeobox genes Mouse chromosomes. Mouse embryo (12 days). Adult mouse. 9.
(10) Sea urchin. 10.
(11) South African Frog (Xenopus laevis). Zebrafish (Danio Renio). 11.
(12) chick Chick. 12.
(13) mouse. plant (Arabidopsis thaliana). 13.
(14) 模式生物的特性 1. 與人類有相似處 (功能相似, 有基因保留性) 2. 易培養 (經費少, 空間小, 生長周期短, 繁殖快, 子代多) 3. 易於實驗操作 (體外受精, 胚體透明, 容易進行基因操控) 4. 資料多 (基因已解碼). 動物發育的主要過程 1. 受精 (Fertilization) 2. 卵裂 (Cleavage) 3. 原腸化 (Gastrulation) 4. 神經 (Neurulation) 5. 器官生成 (Organogenesis) 6. 個體生成 (Growth). 14.
(15) Fertilization • Fertilization brings the haploid nuclei of sperm and egg together, forming a diploid zygote • The sperm’s contact with the egg’s surface initiates metabolic reactions in the egg that trigger the onset of embryonic development. The acrosomal and cortical reactions during sea urchin fertilization. Basal body (centriole) Sperm head. Acrosome Jelly coat Sperm-binding receptors. Vitelline layer Egg plasma membrane. 15.
(16) The acrosomal and cortical reactions during sea urchin fertilization. Basal body (centriole) Sperm head. Hydrolytic enzymes. Acrosome Jelly coat. Vitelline layer. Sperm-binding receptors. Egg plasma membrane. The acrosomal and cortical reactions during sea urchin fertilization. Sperm nucleus Acrosomal process Basal body (centriole) Sperm head. Acrosome Jelly coat Sperm-binding receptors. Actin filament. Hydrolytic enzymes Vitelline layer Egg plasma membrane. 16.
(17) The acrosomal and cortical reactions during sea urchin fertilization. Sperm plasma membrane Sperm nucleus Acrosomal process Basal body (centriole) Sperm head. Actin filament. Fused plasma membranes Hydrolytic enzymes. Acrosome Jelly coat. Vitelline layer. Sperm-binding receptors. Egg plasma membrane. The acrosomal and cortical reactions during sea urchin fertilization. Sperm plasma membrane Sperm nucleus. Fertilization envelope. Acrosomal process Basal body (centriole) Sperm head. Acrosome Jelly coat Sperm-binding receptors. Actin filament Cortical Fused granule plasma membranes Perivitelline Hydrolytic enzymes space Vitelline layer Egg plasma membrane. EGG CYTOPLASM. 17.
(18) Cleavage. (a) Fertilized egg. (b) Four-cell stage. (c) Early blastula. (d) Later blastula. 18.
(19) Dorsal. The body axes and their establishment in an amphibian. Right. Anterior. Posterior. Left. 體軸 前/後軸(A/P axis) 背/腹軸(D/V axis) 左/右軸(L/R axis). Ventral (a) The three axes of the fully developed embryo Animal pole Animal hemisphere. Vegetal hemisphere. Point of sperm nucleus entry. Pigmented cortex. First cleavage. Future dorsal side. Gray crescent. Vegetal pole (b) Establishing the axes. 19.
(20) Cleavage in a frog embryo. Zygote. Cleavage in a frog embryo. 2-cell stage forming. 20.
(21) Cleavage in a frog embryo. 4-cell stage forming. Cleavage in a frog embryo. 8-cell stage. Animal pole. Vegetal pole. 21.
(22) Cleavage in a frog embryo. Blastocoel Blastula (cross section). Cleavage in a frog embryo 0.25 mm. Animal pole. Zygote. 2-cell stage forming. 4-cell stage forming. 0.25 mm. Blastocoel. Vegetal 8-cell pole Blastula stage (cross section). 22.
(23) 動物發育的主要過程 1. 受精 (Fertilization) 2. 卵裂 (Cleavage) 3. 原腸化 (Gastrulation) 4. 神經 (Neurulation) 5. 器官生成 (Organogenesis) 6. 個體生成 (Growth). Gastrulation in a sea urchin embryo Future ectoderm Future mesoderm Future endoderm Animal pole Blastocoel Mesenchyme cells. Vegetal plate. Vegetal pole. 23.
(24) Gastrulation in a sea urchin embryo Future ectoderm Future mesoderm Future endoderm. Gastrulation in a sea urchin embryo Future ectoderm Future mesoderm Future endoderm Filopodia pulling archenteron tip Archenteron. 24.
(25) Gastrulation in a sea urchin embryo Future ectoderm Future mesoderm Future endoderm. Blastocoel Archenteron Blastopore. Gastrulation in a sea urchin embryo Future ectoderm Future mesoderm Future endoderm Ectoderm. Mouth Mesenchyme (mesoderm forms future skeleton). Digestive tube (endoderm). Anus (from blastopore). 25.
(26) Gastrulation in a sea urchin embryo Key Future ectoderm Future mesoderm Future endoderm Archenteron Animal pole. Blastocoel. Blastocoel. Filopodia pulling archenteron tip. Blastocoel Archenteron Blastopore. Mesenchyme cells Ectoderm Vegetal plate. Vegetal pole. Mouth. Blastopore. 50 µm. Mesenchyme Mesenchyme cells (mesoderm forms future skeleton). Digestive tube (endoderm). Anus (from blastopore). • Gastrulation in the frog – The frog blastula is many cell layers thick – Cells of the dorsal lip originate in the gray crescent and invaginate to create the archenteron – Cells continue to move from the embryo surface into the embryo by involution – These cells become the endoderm and mesoderm – The blastopore encircles a yolk plug when gastrulation is completed – The surface of the embryo is now ectoderm, the innermost layer is endoderm, and the middle layer is mesoderm. 26.
(27) CROSS SECTION. SURFACE VIEW Animal pole Blastocoel. Dorsal lip of blastopore. Dorsal lip of blastopore. Blastopore Early gastrula. Vegetal pole. Blastocoel shrinking. Archenteron. Ectoderm Blastocoel remnant. Mesoderm Endoderm. Archenteron Key Blastopore. Future ectoderm Future mesoderm Future endoderm. Late gastrula. Blastopore. Yolk plug. Endometrial epithelium (uterine lining) Uterus. Inner cell mass Trophoblast. Maternal blood vessel. Blastocoel. Amnion Chorion Ectoderm Mesoderm Endoderm Yolk sac Extraembryonic mesoderm Allantois. 27.
(28) neurulation Eye. Neural folds. Somites. Tail bud. Neural plate. Neural fold. SEM 1 mm. 1 mm. Notochord. Neural crest cells. Coelom. Somite. Neural tube. Neural Neural fold plate Neural crest cells. Notochord Ectoderm. Archenteron (digestive cavity). Outer layer of ectoderm. Mesoderm Endoderm Archenteron. Neural crest cells. (c) Somites. (a) Neural plate formation Neural tube (b) Neural tube formation. ECTODERM Epidermis of skin and its derivatives (including sweat glands, hair follicles) Epithelial lining of mouth and anus Cornea and lens of eye Nervous system Sensory receptors in epidermis Adrenal medulla Tooth enamel Epithelium of pineal and pituitary glands. MESODERM. ENDODERM. Notochord Skeletal system Muscular system Muscular layer of stomach and intestine Excretory system Circulatory and lymphatic systems Reproductive system (except germ cells) Dermis of skin Lining of body cavity Adrenal cortex. Epithelial lining of digestive tract Epithelial lining of respiratory system Lining of urethra, urinary bladder, and reproductive system Liver Pancreas Thymus Thyroid and parathyroid glands. 28.
(29) Organogenesis Limb. kidney. 29.
(30) Blood vessels. Heart. 30.
(31) 發育過程 Pattern formation Morphogenesis Cell differentiation growth. 發育過程之機制 1. Differential gene expression/signaling 2. Cell fate determination 3. Induction 4. Pattern formation a. Positional information b. Lateral inhibition 5. Asymmetric division. 1. Differential gene expression. Representative cell types of a vertebrate cell differentiation. 31.
(32) 2. Cell fate determination Cell transplantation. 2. Cell fate determination GFP labeled or Laser caged. 32.
(33) 2. Cell fate determination Cell-linage analysis. 3. Induction. 33.
(34) 4. Pattern formation a. Positional information. 4. Pattern formation a. Positional information. cell-cell communication. morphogen. a b Set >a : Blue <b : Red. 34.
(35) 2D. 35.
(36) 36.
(37) 4. Pattern formation b. Lateral inhibition. 5. Asymmetric division. 37.
(38) 幹細胞 1.甚麼是幹細胞/ 與發育生物學之關係 2.幹細胞來源 a. 成體幹細胞 (adult stem cell): 骨髓，成體週邊血 (取得極為困難） b. 胚胎幹細胞 (embryonic stem cell): 胚胎，臍帶血 (取得容易). 3. 幹細胞之運用 (複製, 組織再生) 4. 幹細胞研究之道德探討. 38.
(39) 幹細胞 • The tiny cluster of cells is an early-stage human embryo that is being used to isolate stem cells under microinjection (a) and growing in culture (b).. What Are Stem Cells? • Stem cells share two basic characteristics that make them distinctive from other cell types : self-renewal and differentiation into specialized cell types. 39.
(40) Ability of stem cell differentiation. 全能性幹細胞. 複能性幹細胞. 多能性幹細胞. 幹細胞研究之先驅 1998年美國威斯康辛大學的James Thompson以及Johns Hopkins醫 院的John Gearhart兩位教授，成功地將人類多功能性 (pluripotent) 的胚胎幹細胞 (embryonic stem cell) 在體外培養與繁殖，開啟了 全球對於幹細胞研究的熱. 40.
(41) human embryonic stem cells (hESCs). ST Figure 4.3. 幹細胞. 41.
(42) The Major Types of Stem Cells A. Embryonic Stem Cells (胚胎幹細胞 ESC)– 道德！ • From blastocysts left over from In-Vitro Fertilization in the laboratory ---Fetus Stem Cells (胎兒幹細胞)--道德！ • From aborted fetuses ---Umbilical Cord Stem Cells (臍帶幹細胞) B. Adult Stem Cells (成體幹細胞) • Stem cells have been found in the blood, bone marrow, liver, kidney, cornea, dental pulp, umbilical cord, brain, skin, muscle, salivary gland . . . .. 成體幹細胞 (Adult Stem Cell) • 又稱為組織專一幹細胞 (Tissue-specific stem cell) • 取自自體, 免疫相合, 不會排斥 • 無道德倫理爭議 • 增生能力有限, 隨年齡而降低 • 特定分化能力有限制 • 功能與應用上遜於胚胎幹細胞. 42.
(43) 幹細胞依功能分類 –造血幹細胞 (hematopoietic stem cells，HSC) –間葉系幹細胞 (mesenchymal stem cells，MSC) 可分化成軟骨細胞, 骨細胞, 脂肪, 神經, 肝細胞等. ‧ 這兩種幹細胞皆存在於骨髓、嬰兒臍帶血、以及成人週 邊血液中。 ‧ HSC在重建血液及免疫系統的研究中倍受重視 ‧ MSC 在組織再生的臨床應用，則在近年來吸引了許多的 注意力。 ‧ 因無道德倫理爭議, 未來發展潛力大. 分化是不可回頭的發育路徑？ 體細胞可否返老還童？. 43.
(44) Nuclear Reprogramming Approaches for Producing Pluripotent Stem Cells (複製羊). • Stem cells research-regenerative medicine. Parkinson’s disease（巴金森氏症） Alzheimer’s disease（老人癡呆症） Spinal cord injury（脊髓損傷） Stroke（中風） Burns（燒傷） Diabetes（糖尿病） Liver failure（肝衰竭） Heart disease（心臟病） Osteoarthritis（骨關節炎） Rheumatoid arthritis （風濕性關節炎） End-stage kidney disease （末期腎臟病變）. 44.
(45) 以幹細胞修補受損老鼠心肌. 45.
(46) 2008 自體幹細胞培育氣管移植. 血性腦中風患者. 46.
(47) 2001年8月，美國總統布希針對「人類胚胎幹細胞」的議題，同意 美國政府可以有條件地資助幹細胞的研究，但是他限制了胚胎幹細 胞來源必須是現有的64株，不可以再取得新的胚胎幹細胞，他認為 這樣子就沒有毀掉胚胎的疑慮。. 幹細胞,複製與組織再生 • 何謂複製 (cloning) – 是指藉由一個細胞、器官或是去氧核醣核酸 （DNA）持續不斷的分裂成另一個在基因型態 上完全相同的細胞、器官或是去氧核醣核酸的 一種過程。. 47.
(48) 複製生命 (Dolly the sheep) • 複製動物則是把成年動物的一個細胞，植入一個已經拿掉 基因物質的卵子。複製作業整體的成功率不到3％。 • 撇開複製技術的困難度不談，「複製」本身所帶來的社會 倫理衝擊則更引人爭議。. 複製人與器官複製. 複製動物 ‧1997年2月27日英國Roslin 研究所科學家於Nature雜 誌上首先發表複製羊桃莉 (Dolly)複製成功 (Somatic Cell Nuclear Transfer). Nature 385: 810. 48.
(49) 複製羊技術 Somatic cell nuclear transfer (SCNT) Removing the maternal nucleus before nuclear transfer Nuclear transfer embryo about to be activated. 治療性複製 (組織與器官複製) 包括三個部分 1. 核移植 2. 胚胎幹細胞製備（human embryonic stem cell） 3. 控制分化（control of differentiation） –. 目前這三部分都已有了初步成果，雖然離成功尚遠，但以人類 過去科技發展的軌跡來看，既然可行性已獲得證實，則成功率 與改進應指日可待. ‧ 再生醫學(Regenerative Medicine) – 培養細胞與組織，用來修補受損傷的組織與器官 ‧ 細胞、組織、與器官移植. 49.
(50) 組織工程(Tissue Engineering) ‧ 皮膚移植（燒燙傷、美容） ‧ 器官再造 – 1997 Dr. Charles Vacanti (University of Massachusetts) 利用小鼠製造人工義耳 ‧ 以可吸收性聚合物製造耳朵形狀，以牛膠原細胞包覆 ‧ 埋放到裸鼠皮下，生長成人形耳朵 – 其他可能應用：膀胱、腎臟…等. 50.
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