teaser
Anthony P Hollander
PhD
ARC Professor of Rheumatology & Tissue Engineering
University of Bristol UK
E:[email protected]
The start of the 20th century saw the birth of the pharmaceutical industry, which grew exponentially and has dominated therapeutics ever since. However, the start of the 21st century has seen the emergence of cell therapies as an alternative paradigm for treating otherwise intractable diseases. It is too early to say if the therapeutic use of cells will achieve the same degree of success as the use of pharmaceuticals. However, what is already clear is that there is huge potential for achieving important clinical advances. Cartilage repair provides a useful example of a regenerative medicine approach and illustrates the need for advances in our understanding of stem cells.
Regenerative medicine
The aim of regenerative medicine is to restore normal function to organs and tissues that do not function properly as a result of disease, traumatic injury or birth defects.(1) To grow and use an engineered tissue you need to start with the best available cells, put them onto a scaffold material that will help to guide their growth and then find a way of implanting the constructed tissue into the body.(2)
Autologous therapies use the patients’ own cells rather than those from a donor. However, this is expensive because the implants have to be prepared individually under good manufacturing practice (GMP) conditions. Off-the-shelf implants would be cheaper but might carry the risk of immune rejection.
Cartilage repair
Cartilage is an ideal tissue for repair by tissue engineering. It is avascular and aneural.(3) Indeed, the lack of vasculature may underlie its poor capacity to repair when injured. It has only one cell type, the chondrocyte, making it relatively simple to organise from a tissue engineering perspective. Autologous chondrocyte implantation (ACI) was developed as a new technique in the 1990s and has been used increasingly worldwide ever since.(4,5) In the UK, this cell therapy is only available as NHS treatment if it is delivered as part of a research programme or patient registry.
However, this technique can only be used to treat focal lesions in younger people, for example caused by sports and other traumatic injuries.(6) If we are to develop this technology to treat large lesions in older patients with advanced osteoarthritis then we will need to engineer and implant mature cartilage (see Figure 1),(7,8) rather than just providing cells, and we will need to use an alternative cell source because the patient’s own chondrocytes will be diseased and senescent. (9)
[[HPE25_fig1_81]]
Stem cells
Stem cells provide an important alternative to the use of differentiated somatic cells. They are pluripotent (that is, they can differentiate into a wide variety of lineages) and self-renewing.(10,11) However, the degree to which they display these and other key properties depends on their origin (see Table 1).
[[HPE25_table1_80]]
Embryonic stem cells derived from the inner cell mass of blastocysts are quintessentially stem cell-like in that they are totipotent (they can make any cell type) and have an unlimited capacity to divide without becoming senescent. (11–13) These properties make them an attractive tool for developing off-the-shelf cell therapies. However, there are a number of drawbacks to their clinical use. First, they have a propensity to form teratomas when implanted in vivo. Secondly, effective methods for controlled differentiation along specific lineages have yet to be developed. Finally, they are by definition allogeneic cell lines, and immune rejection must be controlled in some way.
Adult stem cells exist within various tissue “niches”, with local environments providing molecular signals that retain the stem cells in a quiescent state and prevent them from further differentiation until they have been released from the niche.(10) For clinical use, they must be isolated from their tissue of origin and separated from other cells. They are not cell lines, and it is probable that autologous cells would be used. This is advantageous because it avoids any problems of immune rejection, but it is expensive to provide for large numbers of patients.
Future prospects
With an ageing population, there will be an increasing clinical need for cell therapies to be used to treat chronic illnesses such as neurodegeneration, cardiovascular diseases, diabetes and musculoskeletal degeneration. Stem cells or somatic cells could be used for tissue regeneration in vitro (tissue engineering) or in vivo (systemic delivery of cells). Clearly, different strategies will be needed for different clinical situations. But whatever the protocol, there will be an increasing need for scaled-up delivery of cells under guaranteed sterile conditions. Ultimately, this might require a larger number of GMP clean laboratories to be built and managed within some hospitals, although for now cell growth is often purchased through private providers. If cost-effective cell-expansion methods can be developed alongside reliable techniques for stem cell differentiation, then a real revolution in healthcare may be possible.
References
- Mironov V, Visconti RP, Markwald RR. What is regenerative medicine? Emergence of applied stem cell and developmental biology. Expert Opin Biol Ther 2004;4:773-81.
- Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920-6.
- Poole AR. Cartilage in health and disease. In: Koopman WJ, editor. Arthritis and allied conditions: a textbook of rheumatology. Baltimore: Williams & Wilkins; 1997. p. 255-308.
- Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-95.
- Peterson L, Minas T, Brittberg M, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop 2000;374:212-34.
- Minas T, Peterson L. Advanced techniques in autologous chondrocyte transplantation. Clin Sports Med 1999;18:13-44, v-vi.
- Kafienah W, Jakob M, Demarteau O, et al. Three dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng 2002;8:817-26.
- Kafienah W, A-Fayez F, Hollander AP, Barker MD. Inhibition of cartilage degradation: a combined tissue engineering and gene therapy approach. Arthritis Rheum 2003;48:709-718.
- Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 2002;3:257-64.
- Mikkers H, Frisen J. Deconstructing stemness. EMBO J 2005;24:2715-9.
- Mayhall EA, Paffett-Lugassy N, Zon LI. The clinical potential of stem cells. Curr Opin Cell Biol 2004;16:713-20.
- Gerecht-Nir S, Itskovitz-Eldor J. Cell therapy using human embryonic stem cells. Transpl Immunol 2004;12:203-9.
- Vats A, Bielby RC, Tolley NS, et al. Stem cells. Lancet 2005;366:592-602.
