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Xu Group Adds Stem Cell Research to Its Bionanotechnology Repertoire

  • Nancy Xu with Kerry Lee of the research group
  • Lauren Browning

For more than a decade, Old Dominion University bionanotechnology researcher X. Nancy Xu and her research group have been finding innovative ways to conduct nanoparticle probes of living cells and embryos. This work, which opens the way for new medical therapies, has brought Xu millions of dollars in research funding and numerous awards and honors.

Now, the team is directing its creative energies toward yet another fundamental challenge in biotechnology research - this one involving embryonic stem cells (ESCs) and nanosecond pulses of electric fields.

Xu and two of her team members, doctoral student Lauren Browning and research scientist Tao Huang, reported in the June issue of Biotechnology Journal that they have found a novel way to create and sustain the undifferentiated ESCs that scientists need for numerous research projects.

This article is one of six research articles that have been published this year by Xu, professor of chemistry and biochemistry at ODU, and her research group. One published earlier in the spring in the journal Nanoscale reports research results indicating that carefully regulated doses of silver nanoparticles can infiltrate cancer cells and inhibit their growth and division.

But the stem cell research opens a new frontier for the Xu group. The pluripotent nature of ESCs explains why medical researchers are so interested in them. These are the basic cells that can reproduce and differentiate, becoming the full array of specialized cells found in a living creature. In other words, from the basic human ESCs, a heart develops, so do the eyes and toes, and so forth.

Therefore, ESC-based therapies potentially could treat many diseases and disorders.

Before medical miracles can be realized, however, some fundamental problems must be solved. Scientists don't yet understand how ESCs differentiate, much less how differentiation can be guided specifically and put to use. (As examples of the uses, ESCs might be implanted in a person with a diseased heart to create new, healthy heart muscle, or used to create new nerve cells for a person with Alzheimer's disease.)

To better under how ESCs work, scientists need to spend a lot of time probing undifferentiated live cells. Unfortunately, ESCs do not want to cooperate; their nature is to differentiate. Without controlling the specific differentiation of ESCs, they would not differentiate into useful tissues and organs.

Currently, undifferentiated ESCs are cultured on a layer of feeder cells that are alive, but which have been altered internally so that they are growth-arrested, or mitotically inactive. To accomplish the alteration of feeder cells, laboratories have used gamma radiation and chemical inactivation. Both techniques are problematic, hindering the progress of ESC research.

Xu and her team report that they have used a conventional - and inexpensive - electroporator to prepare rainbow trout spleen cells as feeder cells for ESCs of zebrafish without the need for gamma radiation or chemicals. The cells were exposed to sequences of very short electric pulses, and the result, according to the researchers, were "high-quality, growth-arrested feeder cells for proliferation of undifferentiated ESC over time."

"To our knowledge, this is the first time the pulsed electric fields have been used to prepare growth-arrested feeder cells for culturing ESCs," Xu said. She called the technique "simple, green and effective."

The researchers believe the technique can be tuned, according to the length and electric-field strength of the electric pulses, to produce various types of growth-arrested cells. They also reported that they now are examining the molecular mechanisms of the effects of pulsed electric fields on the cells.

The paper in Biotechnology Journal is the sixth research article published so far in 2010 by Xu and her research group. Other recent articles were in the journals:

• Nanoscale: doctoral student Nallathamby, and Xu, authored "Study of Cytotoxic and Therapeutic Effects of Stable and Purified Silver Nanoparticles on Tumor Cells."

• Biochemistry: doctoral students Nallathamby, Kerry Lee and Tanvi Desai, and Xu authored "Study of Multidrug Membrane Transporter of Single Living Pseudomonas aeruginosa Cells Using Size-Dependent Plasmonic Nanoparticle Optical Probes."

• Analytical and Bioanalytical Chemistry: doctoral students Lee, Browning, Nallathamby and Feng Ding; Huang, and Xu authored "Probing of Multidrug ABC Membrane Transporters of Single Living Cells Using Single Plasmonic Nanoparticle Optical Probes."

Research reported in these articles advances the groups work fashioning effective silver and gold nanoparticles that can enter cells to essentially light up intracellular functions or perform other missions.

The article in Nanoscale demonstrates the possibility of using silver nanoparticles to inhibit the growth and division of tumor cells, and using the particles' cytotoxicity for potential therapeutic treatments. The study reported in the paper also provides a new method to count the number of single nanoparticles in a medium for characterization of their concentration and stability at single nanoparticle resolution over time.

Another important part of this work examines multi-drug resistance of cells. ATP-binding cassette (ABC) membrane transporters - also called efflux pumps - function in live cells as gatekeepers or bouncers; they are wired to arrest and spit out foreign objects that get inside the cells. So they often bounce nanoparticles, as well as molecules of medicinal chemicals (e.g., antibiotics and chemotherapeutic drugs). By using the size-dependent optical properties of nanoparticles, the Xu group is using these nanoparticle probes to investigate the mechanisms and functions of these multi-drug membrane transporters, which is needed for rational design of effective therapy, including smart drug delivery.

With more study, the day may come when chemotherapies could have stealth qualities. Molecules of medicine would be able to enter cells and avoid the ABC transporters long enough to perform their mission. This would allow precise and effective targeting of cancer cells and avoid the current massive doses of medicines needed to outgun the transporters.

For example, the article in Biochemistry states: "We found that the smaller nanoparticles stayed inside the cells longer than larger nanoparticles, suggesting the size-dependent efflux kinetics of the cells. This study shows that multi-sized nanoparticles can be used to mimic various sizes of antibiotics for probing the size-dependent efflux kinetics of multidrug membrane transporters in single living cells."

Xu has received more than $3 million in grants from the National Institutes of Health and the National Science Foundation since 2005 for her groundbreaking research.

This article was posted on: July 6, 2010

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