Current state of regenerative medicine: moving stem cell research from animals into humans for clinical trials

San Diego Regenerative Medicine Institute and Xcelthera INC announce Dr. Parsons several recent publications for our progresses towards clinical translation of human embryonic stem cell research.

Protocol: Direct conversion of pluripotent hESCs under defined culture conditions into human neuronal or cardiomyocytes cell therapy derivatives. Methods Mol. Biol. 2014, Feb. 6. Chapter in Human Embryonic Stem Cells: Methods and Protocols, 2^nd Edition. Springer’s Protocols. DOI: 10.1007/7651_2014_69. PMID24500898.

Public Preview: Developing novel strategies for well-controlled efficiently directing pluripotent human embryonic stem cells (human ES cells) exclusively and uniformly towards clinically-relevant cell types in a lineage-specific manner is not only crucial for unveiling the molecular and cellular cues that direct human embryogenesis, but also vital to harnessing the power of human ES cell biology for tissue engineering and cell-based therapies. Conventional human ES cell differentiation methods require uncontrollable simultaneous multi-lineage differentiation of pluripotent cells, which yield embryoid bodies (EB) or aggregates consisting of a mixed population of cell types of three embryonic germ layers, among which only a very small fraction of cells display targeted differentiation, impractical for commercial and clinical applications. This Springer’s protocol details the step-by-step procedure of PluriXcel technology for lineage-specific differentiation of pluripotent human ES cells, maintained under defined culture systems, direct from the pluripotent stage using small molecule induction exclusively and uniformly to a neural or cardiac lineage. Lineage-specific differentiation of pluripotent hESCs by small molecule induction enables well-controlled high efficient direct conversion of non-functional pluripotent human ES cells into a large supply of high purity functional human neuronal or cardiomyocyte cell therapy derivatives for commercial and therapeutic uses, marking a turning point in cell-based regenerative medicine from current studies in animals towards human trials or first-in-human studies.

Editorial: The designation of human cardiac stem cell therapy products for human trials.  J. Clin. Trial Cardiol. 2014;1(1):02.

Public Preview: For successful pharmaceutical development of stem cell therapy, the human stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials. Moving stem cell research from current studies in animals into human trials must address such practical issues for commercial and therapeutic uses: 1) such human stem cells and/or their cell therapy derivatives/products must be able to be manufactured in a commercial scale; 2) such human stem cells and their cell therapy derivatives/products must be able to retain their normality or stability for a long term; and 3) such human stem cells and/or their cell therapy derivatives/products must be able to differentiate or generate a sufficient number of the specific cell type or types in need of repair or regeneration. Those practical issues are essential for designating any human stem cells as human stem cell therapy products for investigational new drug (IND)-filing and entry into human trials. Our Xcel prototypes of human stem cell therapy products have been developed specifically to address and overcome those major obstacles or issues in clinical applications of human ES cell therapeutic utility, including the benefits in high efficiency, stability, low tumor risk, high purity, high efficacy in repair, as well as safety and large-scale production of high quality human cell therapy products in cGMP facility for commercial and therapeutic uses over all other existing approaches.

Editorial: The openness of pluripotent epigenome – defining the genomic integrity of stemness for regenerative medicine. Int. J. Cancer Ther. Oncol. 2014;2(1):020114. DOI: 10.14319/ijcto.0201.14.

Public Preview: Human embryonic stem cells (human ES cells), derived from the pluripotent inner cell mass or epiblast of the human blastocyst or human embryos, are pluripotent, holding tremendous potential for restoring human tissue and organ function. However, not all pluripotent cells are stem cells. The scientific definition and proof for human pluripotent stem cells are that they have the intrinsic ability of both unlimited or long-term self-renewal and unrestricted differentiation into all the somatic cell types in the human body. So far, there is no evidence that pluripotent cells derived from other sources harboring adult nuclei by transcription-factor- or small-molecule-based reprogramming or somatic cell nuclear transfer, such as iPS cells or pluripotent cells derived from cloned embryos, can maintain prolonged normal stable growth or self-renewal. The artificially reprogrammed adult cells are characterized by the expression of embryonic markers that are initially identified in embryonic tumor/cancer cells and forming teratomas in vivo, which shows these reprogrammed adult cells might be either pluripotent stem cells or pluripotent cancer cells. In contrast, human ES cells 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 open epigenome of pluripotent human ES cells. The openness of pluripotent epigenome differentiates the active pluripotency of normal human ES cells from the repressive pluripotency of abnormal cells, such as the iPS cells reprogrammed from adult cells, pluripotent cells derived from cloned embryos, and pluripotent embryonic carcinoma cells. In view of the growing interest in the use of human pluripotent stem cells, these major drawbacks have raised serious concerns about the genomic integrity of artificially reprogrammed adult cells and, thus, have diminished the utility of reprogramming somatic cells as viable therapeutic approaches. So far, the pluripotent human ES cells remain as the only genetically-stable human pluripotent stem cell source with full-developmental potential in deriving somatic elements for tissue and function restoration.

Critical Review: Current state of regenerative medicine: moving stem cell research from animals into humans for clinical trials. JSM Regen Med 2014;1(1):1005 & Open Access Stem Cell 2014.

Public Preview: Given the limited capacity of the central nervous system (CNS) and the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal tissue and function for neurological and cardiovascular disorders. Derivation of human embryonic stem cell (human ES cells) from the in vitro fertilization (IVF) leftover embryos has brought a new era of cellular medicine for the damaged CNS and heart. Recent advances and technology breakthroughs in human ES cell research have overcome some major obstacles in moving stem cell research from animals towards humans trials, including resolving minimal essential human requirements for de novo derivation and long-term maintenance of clinically-suitable stable human ES cell lines and direct conversion of such pluripotent human ES cells into a large supply of clinical-grade functional human neuronal or cardiomyocyte cell therapy products. Such breakthrough stem cell technologies have demonstrated the direct pharmacologic utility and capacity of human ES cell therapy derivatives for human CNS and myocardium regeneration and, thus, have presented the human ES cell therapy derivatives as a powerful pharmacologic agent of cellular entity for CNS and heart repair. The availability of human stem/progenitor/precursor cells in high purity and large commercial scales with adequate cellular neurogenic or cardiogenic capacity will greatly facilitate developing safe and effective cell-based regenerative therapies against a wide range of CNS and heart disorders. Transforming non-functional pluripotent human ES cells into fate-restricted functional human cell therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of human ES cell-derived cellular products, marking a turning point in cell-based regenerative medicine from current studies in animals towards human trials.