Nanotechnologybased Stem Cell Therapies for Damaged Heart Muscles

Regenerative medicine is an area in which stem cells hold great promise for overcoming the challenge of limited cell sources for tissue repair. Stem cell research is being pursued vigorously in the hope of achieving major medical breakthroughs. Scientists are striving to create therapies that rebuild or replace damaged cells with tissues grown from stem cells, offering hope to people with cancer, diabetes, cardiovascular disease, spinal cord injuries, and many other disorders.

Embryonic stem cells are pluripotent. That means that during normal embryogenesis—the process by which the embryo is formed and develops—

human embryonic stem cells can differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. Researchers have also found undifferentiated cells (adult stem cells) in children and adults. Unlike embryonic stem cells, the use of adult stem cells in research and therapy is not controversial because the production of adult stem cells does not require the creation or destruction of an embryo.

Often, adult stem cells are not pluripotent but multipotent. That means they can differentiate only into a limited variety of cell types. One example is mesenchymal stem cells (MSC)—adult stem cells found in bone marrow that can be differentiated into bone, cartilage, fat, and connective tissues. These offer tremendous potential for the repair and or regeneration of damaged tissues and organs.

An area of particular interest is differentiation of MSC into cardiomyocytes for damaged heart muscle tissue. During a heart attack, part of the heart muscle loses its blood supply and cells in that part of the heart die, thereby damaging the muscle. This reduces the ability of the heart to pump blood around the body. Considering that coronary heart disease is the leading cause of death in most developed countries, stem cell therapy that repairs heart muscle cells and restores the viability and function of the area already damaged could have a tremendous impact on modern medicine.

''Recently, CNTs have been generating great excitement in the fields of bioengineering and drug delivery research. However, very little is known about the affect of CNTs on MSC response,'' says Valerie Barron. ''Therefore, the main goal of one of our research studies was to investigate the effect of CNTs on human MSC (hMSC) biocompatibility, proliferation, and multipotency.''

Barron, a senior researcher at the National Centre for Biomedical Engineering Science at National University of Ireland (NUI), together with collaborators from NUI's Regenerative Medicine Institute and Department of Anatomy, investigated a range of different types of CNTs, including singlewalled nanotubes (SWCNTs), multiwalled nanotubes (MWCNTs), and func-tionalized CNTs.

The scientists revealed that at low concentrations of SWCNTs functionalized with carboxylic acids (COOH), the CNTs had no significant effect on cell viability or proliferation. In addition, by fluorescently labeling the COOH-functionalized SWCNTs, the CNTs were seen to migrate to a nuclear location within the cell after 24 h, without adversely affecting the cellular ultrastructure. Moreover, the nanotubes had no affect on adipogenesis (the development of fat cells), chondrogenesis (the development of cartilage), or osteogenesis (the development of bone).

Previous research had shown that CNTs migrate into cancer cells and can therefore be used for delivery of biomolecules directly into the cells. Barron's study is the first to examine the effect of CNTs on hMSC and as such is important for new and emerging technologies in drug delivery, tissue engineering, and regenerative medicine. It appears that at low concentrations, CNTs have minimal affect on MSC viability and multipotency. Therefore, they have great potential to advance the field in a number of ways, including

1. Manipulation of MSC differentiation pathways

2. Development of nanovehicles for delivering biomolecule-based cargoes to mesenchymal stem cells

3. Creation of novel biomedical applications for electroactive carbon nanotubes in combination with mesenchymal stem cells.

In a previous position at Trinity College Dublin, Barron had worked in Werner Blau's Molecular Electronics and Nanotechnology group where she gained a tremendous appreciation for CNTs. ''As a biomaterials scientist, I could see their potential in biomedical applications,'' she says. At NUI Galway she teamed up with Mary Murphy, a principal investigator in the Orthobiologics Group at the university's Regenerative Medicine Institute, to examine the effect of CNTs on MSC differentiation. Both researchers were aware that, since no clinical therapy is available for the repair of damaged heart muscle, there exist tremendous opportunities for the creation of novel nano-technology-based therapies.

CNTs are electrically conductive and this provides the potential for manipulating MSC differentiation pathways to create electroactive cells such as those found in the heart. In particular, specific applications could result in novel MSC-based cell therapies for electroactive tissue repair; novel biomolecule delivery vehicle for manipulation of MSC differentiation pathways; and elec-troactive CNT scaffolds for damaged electroactive tissues.

''At present, we are developing a novel electrophysiological environment to promote MSC differentiation towards a cardiomyocyte lineage,'' says Barron. ''In the short term, we plan to focus on optimizing this approach to develop nanotechnology-based cell therapies. In the longer term we hope to use the CNTs as delivery vehicles for a range of different biomolecules for the manipulation of MSC differentiation pathways towards a range of different cell types.''

Featured scientist: Valerie Barron

Organization: National Centre for Biomedical Engineering Science at

National University of Ireland, Galway (Ireland) Relevant publication: Emma Mooney, Peter Dockery, Udo Greiser, Mary Murphy, Valerie Barron: Carbon nanotubes and mesenchymal stem cells: biocompatibility, proliferation and differentiation, Nano Lett., 8, 2137-2143.

CHAPTER 11

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