Lowering the increased intracellular pH of human-induced pluripotent stem cell-derived endothelial cells induces formation of mature Weibel-Palade bodies.,STEM CELLS Translational Medicine

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Lowering the increased intracellular pH of human-induced pluripotent stem cell-derived endothelial cells induces formation of mature Weibel-Palade bodies.
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2020-03-12 , DOI: 10.1002/sctm.19-0392
Gesa L Tiemeier ₁ , Rozemarijn de Koning ₁ , Gangqi Wang ₁ , Sarantos Kostidis ₂ , Rosalie G J Rietjens ₁ , Wendy M P J Sol ₁ , Sébastien J Dumas _{3,

4} , Martin Giera ₂ , Cathelijne W van den Berg ₁ , Jeroen C J Eikenboom ₅ , Bernard M van den Berg ₁ , Peter Carmeliet _{3,

4} , Ton J Rabelink ₁

Affiliation

Differentiation of human‐induced pluripotent stem cells (hiPSCs) into vascular endothelium is of great importance to tissue engineering, disease modeling, and use in regenerative medicine. Although differentiation of hiPSCs into endothelial‐like cells (hiPSC‐derived endothelial cells [hiPSC‐ECs]) has been demonstrated before, controversy exists as to what extent these cells faithfully reflect mature endothelium. To address this issue, we investigate hiPSC‐ECs maturation by their ability to express von Willebrand factor (VWF) and formation of Weibel‐Palade bodies (WPBs). Using multiple hiPSCs lines, hiPSC‐ECs failed to form proper VWF and WPBs, essential for angiogenesis, primary and secondary homeostasis. Lowering the increased intracellular pH (pHi) of hiPSC‐ECs with acetic acid did result in the formation of elongated WPBs. Nuclear magnetic resonance data showed that the higher pHi in hiPSC‐ECs occurred in association with decreased intracellular lactate concentrations. This was explained by decreased glycolytic flux toward pyruvate and lactate in hiPSC‐ECs. In addition, decreased expression of monocarboxylate transporter member 1, a member of the solute carrier family (SLC16A1), which regulates lactate and H+ uptake, contributed to the high pHi of hiPSC‐EC. Mechanistically, pro‐VWF dimers require the lower pH environment of the trans‐Golgi network for maturation and tubulation. These data show that while hiPSC‐ECs may share many features with mature EC, they are characterized by metabolic immaturity hampering proper EC function.

中文翻译：

降低人类诱导的多能干细胞来源的内皮细胞的升高的细胞内pH值会诱导形成成熟的Weibel-Palade体。

将人诱导的多能干细胞（hiPSC）分化为血管内皮对组织工程，疾病建模以及在再生医学中的应用非常重要。尽管以前已经证明了hiPSC分化为内皮样细胞（hiPSC衍生的内皮细胞[hiPSC-ECs]），但关于这些细胞如实反映成熟内皮的程度仍存在争议。为了解决此问题，我们通过hiPSC-ECs表达von Willebrand因子（VWF）和Weibel-Palade体（WPBs）形成的能力来研究其成熟度。使用多个hiPSCs品系，hiPSC-EC无法形成适当的VWF和WPB，这对于血管生成，原发性和继发性体内平衡至关重要。用乙酸降低hiPSC-ECs升高的细胞内pH（pHi）确实导致了伸长的WPB的形成。核磁共振数据表明，hiPSC-ECs中较高的pHi与细胞内乳酸浓度降低有关。这可以通过hiPSC-ECs中对丙酮酸和乳酸的糖酵解通量降低来解释。另外，调节溶质和H +吸收的溶质载体家族（SLC16A1）的一元羧酸转运蛋白成员1的表达降低，导致hiPSC-EC的pHi高。从机械上讲，前VWF二聚体需要较低的pH环境。调节乳酸和H +的吸收，导致hiPSC-EC的高pHi。从机械上讲，前VWF二聚体需要较低的pH环境。调节乳酸和H +的吸收，导致hiPSC-EC的高pHi。从机械上讲，前VWF二聚体需要较低的pH环境。反式高尔基体网络，用于成熟和输卵管。这些数据表明，虽然hiPSC-EC与成熟的EC可能具有许多共同的特征，但它们的特征是代谢不成熟，妨碍了正常的EC功能。

更新日期：2020-03-12

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