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A study of the effect of physical cues on stem cell fate determination

  • Author(s): Chao, Tzu-I
  • Advisor(s): Lu, Jennifer
  • et al.
Abstract

Stem cell research has been fueled by increasing evidence of their great promise in clinical regenerative therapy. Conventionally, stem cell fate determination can be attributed to genetic and biochemical factors. However, the field has started to recognize the importance of the stem cell microenvironments that provide physical cues to influence cell fate decision. From a tissue engineer’s point of view, introducing physical factors to the differentiation process could be an approach to direct stem cell fate. This concept is supported by a growing body of evidence showing the responsiveness of stem cells to physical stimuli. I thus develop two platforms to study the effect of (a) static environmental cues and (b) dynamic mechanical loading on stem cell fate decisions. Carbon nanotubes (CNTs), which possess relevant features such as (1) dimension analogous to that of natural extracellular matrix (ECM) molecules, (2) large surface area, and (3) ability to serve as nano-heaters to convert absorbed near-infrared (NIR) radiation into heat, were used to fabricate artificial stem cell niches. I exploit properties (1) and (2) of CNTs to make a biocompatible thin film with large surface area, to promote growth factor adsorption and preferential stem cell differentiation. Enhanced neuron differentiation from human embryonic stem cells (hESCs) was observed in poly(methacrylic acid) (PMAA)-functionalized CNT (PMAA-g-CNT) thin films. Polarized expression of motor neuron-specific marker, synapsin 1, was also detected in cells differentiatedon PMAA-g-CNT surfaces. Cells survive in this platform, with no detrimental effects observed. The improved differentiation can be attributed to the increased surface area created by the nanofibrillar structure, leading to enhanced growth factor adsorption. This is the first study to indicate that increasing surface area by use of CNT substrates leads to enhanced growth factor adsorption and stem cell differentiation. To shed light on how mechanical stimulation instructs cell fate decision, preliminary work has also been done to develop a remote-controlled nanohybrid actuator system to apply dynamic mechanical stimulation to stem cells. This is achieved by employing the thermal responsive nature of poly(N-isopropylacrylamide) (PNIPAM), and the unique ability of CNTs to absorb NIR. The actuation of PNIPAM hydrogel can be triggered by temperature change, while the cells on the PNIPAM actuator change in cell shape and size upon sensing the mechanical stimulation. CNTs embedded in the polymer matrix convert photon energy into heat and initiate the contraction of PNIPAM gel. The novel device can sense NIR inputs and showed noticeable shrinkage after NIR stimulation. It can therefore be used to apply remotely controlled mechanical loads to stem cells for cell behavior study. Cytosolic calcium fluctuations, which play an important role in cell differentiation and are sensitive to mechanical stimulation, may thus be tuned by using the novel actuator to achieve controlled cell differentiation. My work described above paves a way for further studies to investigate the effect of mechanical inputs on stem cell fate decision.

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