San Diego
Regenerative Medicine Institute and Xcelthera
announce the publication of Dr. Parsons’ original research article supported by
the National Institutes of Health, titled “Human Stem Cell Derivatives Retain
More Open Epigenomic Landscape When Derived from Pluripotent Cells than from
Tissues”,
in Journal of Regenerative Medicine at http://dx.doi.org/10.4172/2325-9620.1000103
& http://scitechnol.com/jrgmhome.php.
The growing number of
identified stem cell derivatives and escalating concerns for safety and
efficacy of these cells towards clinical applications have made it increasingly
crucial to be able to assess the relative risk-benefit ratio of a given stem
cell from a given source for a particular disease. Genomic and proteomic
profiling in isolation has not provided such a
tool. Gene expression analysis has indicated that stem cell derivatives
do not seem to have a common core transcription profile that dictates the
undifferentiated self-renewing state, which suggests that gene expression alone
is not sufficient to define either intrinsic plasticity or developmental
potential of a given stem cell. A search for a common set of transcribed genes
that defines the characters of all stem cell derivatives, known as stemness,
has been unsuccessful; there is virtually no overlap in the gene expression
profiles of various types or derivations of stem cells, in spite of their
apparent phenotypic similarity. Even the expression of a lineage-defining gene
within stem cells seems to require additional epigenetic cues. It is clear that
epigenetic processes are providing additional regulatory dimensions to stem
cell behavior.
The eukaryotic genome is packaged into a
nucleoprotein complex known as chromatin, in which the DNA helix is wrapped
around an octamer of core histone proteins to form a nucleosomal DNA structure.
Packaging of eukaryotic genome into chromatin confers higher order structural
control over the lineage programming processes. Discerning the intrinsic plasticity
and regenerative potential of human stem cell populations might reside in
chromatin modifications that shape the respective epigenomes of their
derivation routes. Previously, we have generated engraftable
human neuronal progenitors direct from pluripotent human embryonic stem cells
(hESCs) by small molecule induction (hESC-I hNuPs). Unlike the prototypical neuroepithelial-like nestin-positive human neural stem
cells (hNSCs), these in vitro neuroectoderm-derived Nurr1-positive hESC-I hNuPs
are a more neuronal lineage-specific and plastic hESC derivative. In this study,
the global chromatin landscape changes in
pluripotent hESCs and their neuronal lineage-specific derivative hESC-I hNuPs were
profiled using genome-wide mapping and compared to CNS tissue-derived hNSCs. This
study found that the broad potential of pluripotent hESCs is defined by an
epigenome constituted of open conformation of chromatin mediated by a pattern
of Oct-4 global distribution that corresponds closely with those of acetylated
nucleosomes genome-wide. The epigenomic transition from pluripotency to
restriction in lineage choices is characterized by genome-wide increases in histone
H3K9 methylation that mediates global chromatin-silencing and somatic identity.
Tissue-resident CNS-derived hNSCs have acquired a substantial number of additional
histone H3K9 methylation, therefore, more silenced chromatin. These data
suggest that the intrinsic plasticity and regenerative potential of human stem
cell derivatives can be differentiated by their epigenomic landscape features,
and that human stem cell derivatives retain more open epigenomic landscape,
therefore, more developmental potential for scale-up regeneration, when derived
from the hESCs in vitro than from the
CNS tissue in vivo.
Human stem cell transplantation
represents a promising therapeutic approach closest
to provide a cure to restore the lost nerve tissue and function for a wide
range of devastating and untreatable neurological disorders. However, to date, lack
of a clinically-suitable source of engraftable human stem/progenitor cells with
adequate neurogenic potential has been the major setback in developing safe and
effective cell-based therapy as a treatment option for restoring the damaged or
lost CNS structure and circuitry.
The traditional sources of engraftable human stem cells with
neural potential for transplantation therapies have been multipotent human
neural stem cells (hNSCs) isolated directly from the human fetal CNS. Under protocols
presently employed in the field,
the prototypical neuroepithelial-like
nestin-positive hNSCs, either isolated from CNS in vivo or derived from pluripotent
cells in vitro via conventional multi-lineage
differentiation, appear to exert their therapeutic effects primarily by their
non-neuronal progenies through producing trophic and/or neuroprotective
molecules to rescue endogenous dying host neurons, but not related to
regeneration from the graft or host remyelination. Under conventional multi-lineage differentiation
approaches, hESC-derived cellular products consist of a heterogeneous
population of mixed cell types, including fully differentiated cells, high
levels of various degrees of partially differentiated or uncommitted cells, and
low levels of undifferentiated hESCs, posing a constant safety concern when
administered to humans. We recently reported that pluripotent hESCs maintained under a defined platform
can be uniformly converted into a cardiac or neural lineage by small molecule
induction. This technology breakthrough enables
well-controlled generation of a large supply
of neuronal lineage-specific derivatives across the spectrum of developmental
stages direct from the pluripotent state of hESCs with small molecule induction.
This novel lineage-specific differentiation approach by small molecule
induction of pluripotent hESCs not only provides a model system for
investigating human embryogenesis, but also dramatically increases the clinical
efficacy of graft-dependent repair and safety of hESC-derived cellular products.
This study by high-resolution genome-wide mapping of
chromatin modifications in human stem cell derivatives further supported the
view that the tissue-resident CNS-derived hNSCs have acquired more silenced
chromatin, therefore, they are likely resides at a more advanced stage of
development with more limited developmental potential or plasticity for tissue
or organ regeneration. Conversely, the hESC derivatives retain more open
epigenomic landscapes, therefore, they might start at an earlier embryonic
developmental stage with more plasticity for scale-up regeneration.
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