Smart Tools For Pathology Research
Published online at Lab Times.
Tissue engineering comes to the rescue when current models of genetic mutations fail to recapture disease traits. In a pioneering step, the Hardy group in the UK and others have created a repository of patient fibroblasts. This database is a huge welcome to regenerative research.
Genetic defects bear the underpinnings of various neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) and are routinely fished out by genome-wide association studies. Getting hold of patient samples harbouring such notorious mutations is one step forward in finding remedies. John Hardy and colleagues at the Institute of Neurology at University College London, UK have created a repository of patient fibroblast cell lines representing a broad spectrum of pathological mutations. Their collection, described in a recent issue of PLoS ONE, undoubtedly has a multitude of applications in neurodegenerative research and therapy.
To delineate the cellular cascades gone awry in disease, animal models are necessary or at least the mutant protein has to be expressed in heterologous cell types, neither of which represents physiological states. For a solution, researchers exploit the “plasticity” of cellular identity. It is now possible for somatic cells viz. fibroblasts to be successfully reprogrammed into pluripotent stem cells (iPSCs). Patient-derived iPSCs can be terminally differentiated into neurons that are predisposed to ‘pathological’ processes and represent a direct readout of the disease condition.
Patient-iPSCs are highly useful as models of neurodegeneration as they can be differentiated into functional neurons, even when obtained at later stages of the disease or from very old cohorts. Besides, the iPSCs from patient skin cells can be differentiated into neurons that display all the pathological hallmarks of the disease. In view of this, several labs have created pools of disease-specific iPSCs for research.
iPSC technology is not, however, hassle-free. Somatic cell reprogramming has a very low efficiency (less than 1%) and is time-consuming. Further, iPSCs often exhibit tumorigenic properties and genomic instability. A useful paradigm to circumvent these problems is to directly convert patient fibroblasts to functional neurons without reprogramming cells to a pluripotent state. Indeed, fibroblasts from an Alzheimer’s patient, for example, have been successfully differentiated into excitatory neurons and integrated into the mammalian central nervous system. Here again, the differentiated neurons recapture the pathophysiology and hence serve as robust models for regenerative research.
In their expanding repository, John Hardy together with collaborators in Europe and USA have established fibroblast lines from skin biopsies of 67 patients diagnosed with AD, PD, HD, ALS, frontotemporal dementia, dystonia and ataxia. The cell lines spanning a range of causative mutations for each disease have been cryopreserved in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research in Camden, New Jersey.
Photo: Test tubes by Chesapeake Bay Program via Creative Commons License