4.8 Article

The regulation of β-adrenergic receptor-mediated PKA activation by substrate stiffness via microtubule dynamics in human MSCs

期刊

BIOMATERIALS
卷 35, 期 29, 页码 8348-8356

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.06.018

关键词

Mesenchymal stem cell; Substrate stiffness; beta-adrenergic receptor; FRET biosensor; Molecular imaging; Protein kinase A

资金

  1. National Institutes of Health [HL098472, HL109142, GM106403]
  2. National Science Foundation CBET [0846429, 1344298]
  3. Beckman Institute Graduate Student Fellowship
  4. Beckman Institute Postdoctoral Fellowship
  5. Div Of Chem, Bioeng, Env, & Transp Sys
  6. Directorate For Engineering [1344298, 0846429] Funding Source: National Science Foundation

向作者/读者索取更多资源

The mechanical microenvironment surrounding cells has a significant impact on cellular function. One prominent example is that the stiffness of the substrate directs stem cell differentiation. However, the underlying mechanisms of how mechanical cues affect stem cell functions are largely elusive. Here, we report that in human mesenchymal stem cells (HMSCs), substrate stiffness can regulate cellular responses to a beta-adrenergic receptor (beta-AR) agonist, Isoproterenol (ISO). Fluorescence resonance energy transfer-based A-Kinase Activity Reporter revealed that HMSCs displayed low activity of ISO-induced protein kinase A (PICA) signal on soft substrate, whereas a significantly higher activity can be observed on hard substrate. Meanwhile, there is an increasing ISO-induced internalization of beta(2)-AR with increasing substrate stiffness. Further experiments revealed that the effects of substrate stiffness on both events were disrupted by interfering the polymerization of microtubules, but not actin filaments. Mechanistic investigation revealed that inhibiting ISO-induced PICA activation abolished beta(2)-AR internalization and vice versa, forming a feedback loop. Thus, our results suggest that the cellular sensing mechanism of its mechanical environment, such as substrate stiffness, affects its response to chemical stimulation of beta-AR signaling and PKA activation through the coordination of microtubules, which may contribute to how mechanical cues direct stem cell differentiation. (C) 2014 Elsevier Ltd. All rights reserved.

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