Embedding Lineage-Specific Developmental Programs into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells Offers Efficiency in Deriving Cell Therapy Products for the Future of Regenerative Medicine

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ review article, titled “Embedding the Future of Regenerative Medicine into the Open Epigenomic Landscape of Pluripotent Human Embryonic Stem Cells”, in Annual Review & Research in Biology at http://www.sciencedomain.org/issue.php?iid=239&id=9. In this review article, Dr. Parsons gives an insight view on the human stem cell epigenomes in discerning the intrinsic plasticity and regenerative potential of human stem cell derivatives from various sources as well as recent advances on uncovering the developmental programs embedded in neural and cardiac lineage-specific differentiation of pluripotent human embryonic stem cells (hESCs) that lead to efficiency in deriving neural and cardiac elements for cell-based therapies.

Human stem cells are extremely attractive for therapeutic development because they have direct pharmacologic utility in clinical applications, unlike any cells originated from animals and other lower organisms that are only useful as research materials. The human stem cell is emerging as a new type of drug of cellular entity that can offer pharmacological utility and capacity for human tissue and function restoration that the conventional compound drug of molecular entity lacks. However, to date, the 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 therapies for regenerating the damaged or lost central nervous system (CNS) structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Pluripotent hESCs, derived from the pluripotent inner cell mass or epiblast of the human blastocyst, have both the unconstrained capacity for long-term stable undifferentiated growth in culture and the intrinsic potential for differentiation into all somatic cell types in the human body, holding tremendous potential for restoring human tissue and organ function. Given the limited capacity of the CNS and heart for self-repair, transplantation of hESC neuronal and heart cell therapy derivatives holds enormous potential in cell replacement therapy for neurodegenerative and heart diseases that cost the healthcare system > $500 billions annually. There is a large unmet healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for normal tissue and function restoration in many major health problems. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by conventional approaches for generating functional cells from pluripotent cells through uncontrollable, incomplete, and inefficient multi-lineage differentiation. Growing evidences indicate that incomplete lineage specification of pluripotent cells via multi-lineage differentiation often resulted in poor performance of such stem cell derivatives and tissue-engineering constructs following transplantation. The development of better differentiation strategies that permit to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to desired phenotypes is vital for realizing the therapeutic potential of pluripotent hESCs.

The eukaryotic genome is packaged into chromatin, a nucleoprotein complex in which the DNA helix is wrapped around an octamer of core histone proteins to form a nucleosomal DNA structure, known as nucleosome, that is further folded into higher-order chromatin structures with the involvement of other chromosomal proteins. Chromatin modifications, such as DNA methylation and histone modifications, serve as important epigenetic marks for active and inactive chromatin states, thus the principal epigenetic mechanism in early embryogenesis. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations reside in chromatin modifications that shape the respective epigenomes of their derivation routes. The broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin. The hESCs are not only pluripotent, but also incredibly stable and positive, as evident by that only the positive active chromatin remodeling factors, but not the negative repressive chromatin remodeling factors, can be found in the pluripotent epigenome of hESCs. The normality and positivity of hESC open epigenome also differentiate pluripotent hESCs from any other stem cells, such as the induced pluripotent stem cells (iPS cells) reprogrammed from adult cells with known oncogenes and the tissue-resident stem cells. Somatic cell nuclear transfer and transcription-factor-based reprogramming have been used to revert adult cells to an embryonic-like state with extremely low efficiencies. Although pluripotent, the iPS cells and ESC derived from cloned embryos by somatic nuclear transfer are made from adult cells, therefore, adult cell-originated pluripotent cells carry many negative repressive chromatin remodeling factors and unerasable genetic imprints of adult cells that pluripotent hESCs do not have. Somatic cell nuclear transfer and factor-based reprogramming are incapable of restoring a correct epigenetic pattern of pluripotent hESCs, which accounts for abnormal gene expression, accelerated senescence, not graftable, and immune-rejection following transplantation of reprogrammed cells. These major drawbacks have severely impaired the utility of reprogrammed or deprogrammed or direct or trans-differentiated somatic cells as viable therapeutic approaches.


Using hESCs to develop cellular medicine for the brain and the heart must first transform pluripotent hESCs into CNS or heart fate-restricted cell therapy derivatives. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. This technology breakthrough enables high efficient direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate pharmacologic capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate pharmacologic capacity to regenerate neurons and contractile heart muscles that no conventional drug of molecular entity or tissue-derived stem cells can. Embedding lineage-specific genetic and epigenetic programs into the open epigenomic landscape of pluripotent hESCs offers a new dimension for direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. Please read Dr. Parsons’ full open access article at http://www.sciencedomain.org/issue.php?iid=239&id=9.