Abstract
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 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. Given the limited capacity of the CNS and heart for self-repair, there is a large unmet healthcare need to develop stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Derivation of human embryonic stem cells (hESCs) provides a powerful in vitro model system to investigate molecular controls in human embryogenesis as well as an unlimited source to generate the diversity of human somatic cell types for regenerative medicine. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. 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. Retinoic acid was identified as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger a cascade of neuronal lineage-specific progression to human neuronal progenitors and neurons of the developing CNS in high efficiency, purity, and neuronal lineage specificity by promoting nuclear translocation of the neuronal specific transcription factor Nurr-1. Similarly, nicotinamide was rendered sufficient to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs by promoting the expression of the earliest cardiac-specific transcription factor Csx/Nkx2.5 and triggering progression to cardiac precursors and beating cardiomyocytes with high efficiency. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate 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. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-based regenerative medicine to a turning point.
Highlights
Pluripotent human embryonic stem cells 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 [1,2,3]
Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, which yields embryoid body (EB) consisting of a mixed population of cell types that may reside in three embryonic germ layers and results in inefficient, incomplete, and uncontrollable differentiation that is often followed by phenotypic heterogeneity and instability, a high risk of tumorigenicity [1,2,3,4,5,6,7,8,9]
In order to generate a large supply of uniform functional cells for tissue engineering and cell therapy, how to channel the wide differentiation potential of pluripotent human embryonic stem cells (hESCs) efficiently and predictably to a desired lineage has been a major challenge for clinical translation
Summary
Pluripotent human embryonic stem cells (hESCs) 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 [1,2,3]. BFGF (at an optimal concentration of 20 ng/ ml), insulin (20 μg/ml), ascorbic acid (50 μg/ml), laminin, and activin-A (50 ng/ml) were identified as the minimal essential elements for sustaining pluripotence and self-renewal of clonal hESCs in a defined culture system, serving as a platform for de novo derivation of therapeutically-suitable pluripotent hESCs that can be directly induced by small molecules into large supplies of safely engraftable neuronal or cardiac lineage-committed progenies across the spectrum of developmental stages with adequate CNS or myocardial regenerative potential for neural or cardiovascular repair in the clinical setting [3,12,14]. Small molecules used to induce hESC lineage-specific therapy derivatives are usually safe developmental signal molecules and morphogens, it should be cautious of the small molecules used in the reverse process to generate iPS cells or trans-differentiation, which are known toxic cancerogenic chemicals with too dangerous or even lethal side effects to be used for patients [3,21,48,49,63]
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