Biomedical Engineering Reference
In-Depth Information
degeneration of the developing brain (e.g. stroke), it might be necessary to implant
stem/progenitor cells that are seeded on biodegradable matrices [
40
].
There is great excitement about the potential of iPS cells not only for cell
replacement but also for disease modeling. Although iPS cell-based disease
modeling is a newly evolving field with many open questions, the rapid progress
that has been made is remarkable and encouraging. For instance, a flurry of recent
reports has demonstrated that cellular pathology of human diseases can be mod-
eled by using disease- and patient-specific iPS cells [
41
-
45
]. The rationale behind
in vitro disease modeling is to identify a cellular phenotype associated with disease
and to correct this phenotype or defect by drugs, genome editing, or other inter-
ventions. Improved genetic techniques allow site-specific targeting of the human
genome with zinc finger nucleases (ZFN) and transcription activator-like effector
nucleases (TALENs) [
46
,
47
]. Manipulation of defined genetic loci will facilitate
the concurrent design of loss- and gain-of-function experiments using human
pluripotent cells. As a consequence, disease modeling can be performed under
genetically defined conditions with isogenic pluripotent cell lines further
increasing the confidence into the cellular assay and the observed phenotype [
48
].
Nevertheless, the genetic defect alone may not be sufficient to reveal the disease
phenotype during the time frame of an in vitro experiment. Pluripotent cells
typically give rise to young neurons and further maturation may require prolonged
cultivation, which would be a limiting factor for practical applications. To enhance
synaptic differentiation, neuronal differentiation protocols may benefit from more
complex cell culture conditions and biomaterials. Furthermore, since the aging
process is a major risk factor for many neurodegenerative diseases, application of
cellular stressors might be useful to mimic the aging process in a dish [
49
,
50
].
1.5 Cell-based Gene and Drug Therapy
Widespread cellular engraftment into the CNS has been demonstrated for immortal-
ized neural cell lines, progenitor cells isolated from the developing fetal brain, and
neural precursors derived from human ES cells [
51
-
55
]. It is remarkable that these cells
remain highly migratory upon transplantation into the normal and lesioned brain. In
fact, it has been reported that grafted and endogenous NSCs preferentially home to sites
of brain injury [
56
,
57
]. Molecules secreted during the inflammatory response by
immune competent cells (e.g. microglia) and astroglia are the likely chemo-attractant
candidates in this process. For instance, the chemokine stromal cell-derived factor
1-alpha (SDF1-a) has been shown to play an important role in attracting NSCs to
pathology [
58
]. Animal models of various lysosomal storage diseases and myelination
defects benefit from widespread engrafted NSCs [
54
,
55
,
59
]. StemCells Inc., a
California-based company, initiated Phase I clinical trials for Batten disease and
Pelizaeus-Merzbacher disease using their proprietary HuCNS-SC, a cell line originally
derived from human fetal brains [
59
].
The migratory potential of NSCs together with their amenability for genetic
manipulation offers unique opportunities for combining gene and cell therapy [
60
].
