内皮祖细胞的研究进展
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内皮祖细胞是能直接分化为血管内皮细胞的前体细胞
Embryonic EPC
➢ 胚外中胚层卵黄囊血岛 ➢ 与造血干细胞存在共同的前体
Adult EPC
Bone Marrow
(3% BM-MNC)
Peripheral Blood
(0.2% MNC)
Hematopoietic stem cells
Myeloid Precursor
表现为卵黄囊毛细血管内皮形成障碍、 早期造血不能发育
EPCs’ Development
▪ VEGFR and VEGF
➢ Receptor • VEGFR-1 (flt-1) • VEGFR-2 (flk-1/KDR) • VEGFR-3 (flt-4)
➢ Ligand • VEGF、 VEGF-B, C, D, E
EPC CD34+, Flk-1+, AC133+
EC CD34+, Flk-1+, AC133-
CD34-selected culture-dish non-adherent putative EPC (CDNAC) change to a more mature endothelial phenotype during differentiation while the progenitor phenotype remains stable and the monocytic phenotype decreases.
Monocytes
CD14+
CD45+
CD14++ CD45+
Macrophage CD45+
CD14+++
CD133++
CD34+
CD45
?
Mesenchymal stem cells
C-kit-, CD34-
Tissue-resident stem cells
C-kit+
?
?
EPCs
CD133+ KDR+
EPCs myeloid subtype
Endothelial markers+ CD14+
CD34+
?
EPCs
Endothelial markers+
CD133+
Mature EC
CD14low CD34low CD133Endothelial markers+++
Origin and differentiation of endothelial progenitor cells
Department of Pathophysiology Hongmei TAN Nov, 2008
Definition
➢ They are circulating, bone marrow-derived cells that are functionally and phenotypically distinct from mature endothelial cells ➢ They can differentiate into endothelial cells in vitro, as assessed by expression profiles and functional characteristics ➢ They can contribute to in vivo vasculogenesis and / or vascular homeostasis
EPCs’ Development
▪ Tie receptor and ligand：受体酪氨酸激酶家族
➢ Tie-2缺陷的胚胎不能建立血管结构的完整性 ➢ Ang-1缺陷鼠也表现为血管生成缺陷
EPCs’ Development
▪ Ephs family
➢ Erythropoietin producing hepatocyte receptor (Eph) ➢ Ligand: ephrins (Eph A、B) ➢ Eph B可调节 Ang-1 和 Tie-2的表达
促红细胞生成素肝细胞受体及其配体， 是酪氨酸激酶家族中的最大成员。 基因缺失及体外血管形成实验表明： EphB和ephrinB在胚胎血管分化及成人 病理性血管形成中发挥重要作用。
Stem cell
EPC
HSC
Circulating
EPC, EC, HSC CD34+
EPC, EC CD34+, Flk-1+
EPCs’ Development
Molecular Mechanisms
▪ Transcription factor SCL / Tal
是参与原血干细胞分化的基本的转录因子。 A basic helix-loop-helix transcription factor
小鼠SCL基因无效突变的纯合子引起死亡
▪ VEGFR and VEGF
➢ 研究显示VEGFR2缺陷鼠在 E8.5～E9.5时因缺乏 内皮和造血细胞而死亡。
➢ Flk1-/-的胚胎干细胞离体不能分化为EPC。 ➢ 胚胎干细胞向内皮细胞分化对VEGF呈剂量依赖性，
VEGF浓度增加可增加原血干细胞向EPC转化， 而 相应减少造血干细胞的生成。 ➢ VEGFR1纯合突变鼠也因内皮细胞不能形成管样结 构而使胚胎在E9.5～E10死亡。
CD34-selected putative EPC from culture-dish adherent cells (CDAC) express lower levels of endothelial and progenitor markers than CDNAC.
VEGFR-2/Flk-1+
AC133+
CD31+ / Tie-2+
VE-Cadeherin+ / Tie-1+ AC133-Байду номын сангаас
➢ CD34+/ VEGFR-2+ cells can behave as EPCs.
VEGF是唯一已知的在胚胎杂合子状态致死的常染色体基因。
EPCs’ Development
▪ Tie receptor and ligand：受体酪氨酸激酶家族
➢ receptor • Tie-1 (Tie) • Tie-2 (Tek)
➢ Tie-2 ligand：Angiopoietin (Ang，血管生成素 ) • Ang-1：血管内皮化 • Ang-2：血管周围细胞和内皮细胞分离
Embryonic EPC
➢ 胚外中胚层卵黄囊血岛 ➢ 与造血干细胞存在共同的前体
Adult EPC
Bone Marrow
(3% BM-MNC)
Peripheral Blood
(0.2% MNC)
Hematopoietic stem cells
Myeloid Precursor
表现为卵黄囊毛细血管内皮形成障碍、 早期造血不能发育
EPCs’ Development
▪ VEGFR and VEGF
➢ Receptor • VEGFR-1 (flt-1) • VEGFR-2 (flk-1/KDR) • VEGFR-3 (flt-4)
➢ Ligand • VEGF、 VEGF-B, C, D, E
EPC CD34+, Flk-1+, AC133+
EC CD34+, Flk-1+, AC133-
CD34-selected culture-dish non-adherent putative EPC (CDNAC) change to a more mature endothelial phenotype during differentiation while the progenitor phenotype remains stable and the monocytic phenotype decreases.
Monocytes
CD14+
CD45+
CD14++ CD45+
Macrophage CD45+
CD14+++
CD133++
CD34+
CD45
?
Mesenchymal stem cells
C-kit-, CD34-
Tissue-resident stem cells
C-kit+
?
?
EPCs
CD133+ KDR+
EPCs myeloid subtype
Endothelial markers+ CD14+
CD34+
?
EPCs
Endothelial markers+
CD133+
Mature EC
CD14low CD34low CD133Endothelial markers+++
Origin and differentiation of endothelial progenitor cells
Department of Pathophysiology Hongmei TAN Nov, 2008
Definition
➢ They are circulating, bone marrow-derived cells that are functionally and phenotypically distinct from mature endothelial cells ➢ They can differentiate into endothelial cells in vitro, as assessed by expression profiles and functional characteristics ➢ They can contribute to in vivo vasculogenesis and / or vascular homeostasis
EPCs’ Development
▪ Tie receptor and ligand：受体酪氨酸激酶家族
➢ Tie-2缺陷的胚胎不能建立血管结构的完整性 ➢ Ang-1缺陷鼠也表现为血管生成缺陷
EPCs’ Development
▪ Ephs family
➢ Erythropoietin producing hepatocyte receptor (Eph) ➢ Ligand: ephrins (Eph A、B) ➢ Eph B可调节 Ang-1 和 Tie-2的表达
促红细胞生成素肝细胞受体及其配体， 是酪氨酸激酶家族中的最大成员。 基因缺失及体外血管形成实验表明： EphB和ephrinB在胚胎血管分化及成人 病理性血管形成中发挥重要作用。
Stem cell
EPC
HSC
Circulating
EPC, EC, HSC CD34+
EPC, EC CD34+, Flk-1+
EPCs’ Development
Molecular Mechanisms
▪ Transcription factor SCL / Tal
是参与原血干细胞分化的基本的转录因子。 A basic helix-loop-helix transcription factor
小鼠SCL基因无效突变的纯合子引起死亡
▪ VEGFR and VEGF
➢ 研究显示VEGFR2缺陷鼠在 E8.5～E9.5时因缺乏 内皮和造血细胞而死亡。
➢ Flk1-/-的胚胎干细胞离体不能分化为EPC。 ➢ 胚胎干细胞向内皮细胞分化对VEGF呈剂量依赖性，
VEGF浓度增加可增加原血干细胞向EPC转化， 而 相应减少造血干细胞的生成。 ➢ VEGFR1纯合突变鼠也因内皮细胞不能形成管样结 构而使胚胎在E9.5～E10死亡。
CD34-selected putative EPC from culture-dish adherent cells (CDAC) express lower levels of endothelial and progenitor markers than CDNAC.
VEGFR-2/Flk-1+
AC133+
CD31+ / Tie-2+
VE-Cadeherin+ / Tie-1+ AC133-Байду номын сангаас
➢ CD34+/ VEGFR-2+ cells can behave as EPCs.
VEGF是唯一已知的在胚胎杂合子状态致死的常染色体基因。
EPCs’ Development
▪ Tie receptor and ligand：受体酪氨酸激酶家族
➢ receptor • Tie-1 (Tie) • Tie-2 (Tek)
➢ Tie-2 ligand：Angiopoietin (Ang，血管生成素 ) • Ang-1：血管内皮化 • Ang-2：血管周围细胞和内皮细胞分离