Journal of Stem Cell Research & Therapy 

About: Journal of Stem Cell Research & Therapy is an academic journal. The journal publishes majorly in the area(s): Stem cell & Mesenchymal stem cell. It has an ISSN identifier of 2157-7633. It is also open access. Over the lifetime, 533 publications have been published receiving 3585 citations.

Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1

Abstract: Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning. Unexpectedly, conditioning before HSPC infusion was required to protect the mice from lymphoma developing when transplanting small numbers of progenitors. We then designed a one-size-fits-all IL2RG (interleukin-2 receptor common γ-chain) gene correction strategy and, using the same reagents suitable for correction of human HSPC, validated the edited human gene in the disease model in vivo, providing evidence of targeted gene editing in mouse HSPCs and demonstrating the functionality of the IL2RG-edited lymphoid progeny. Finally, we optimized editing reagents and protocol for human HSPCs and attained the threshold of IL2RG editing in long-term repopulating cells predicted to safely rescue the disease, using clinically relevant HSPC sources and highly specific zinc finger nucleases or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9). Overall, our work establishes the rationale and guiding principles for clinical translation of SCID-X1 gene editing and provides a framework for developing gene correction for other diseases.

What is a Master Regulator

Abstract: Copyright: © 2013 Chan SSK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The term “master regulator” or “master regulatory gene” was first coined by Susumu Ohno over 30 years ago for a “gene that occupies the very top of a regulatory hierarchy,” which, “by its very definition should not be under the regulatory influence of any other gene” [1]. While this term was originally proposed to hypothesize a sex determination mechanism, it was subsequently extended to other disciplines to describe the hierarchy of cell specification in yeasts [2,3], Drosophila [4,5] and plants [6]. Although sex determination could conceivably be imagined to be independent of prior regulatory influences, cell type specification clearly requires some sort of prior regulatory influence, and although “other genes” per se might not have been imagined upstream in the earliest usages of the term, as mechanisms of transcriptional control of development were revealed, this original concept of a gene with nothing upstream was forgotten. However the term “master regulator” stayed attached to these earliest developmental specification factors. The meaning evolved to connote governance over a developmental lineage, but without a proper definition as to what sort of governance specifically was referred to. If any gene that is necessary for the establishment of a given lineage is a master regulator, then the genome might have more masters than servants. On the other hand, if the term master can only be applied when a single unique factor governs a specific lineage, then almost no lineages might qualify to have a master regulator. Use of the term is increasing: Google Scholar identifies 139 publications containing the phrase “master regulator” from 1997 and slightly over 7,000 from 2012. Tracking the presence of the term “master regulator” within all publications that mention the term “regulator” over the past decade and a half demonstrates further how popular the term has become (Figure 1), perhaps to the detriment of scientific clarity. Given that the term is not likely to go away, it would be valuable to agree on parameters of definition that would incorporate the current general sense of meaning, but also provide specificity.

Cancer Stem Cells: Cellular Plasticity, Niche, and its Clinical Relevance.

Abstract: Cancer handles an estimated 7.6 million deaths worldwide per annum. A recent theory focuses on the role Cancer Stem Cells (CSCs) in driving tumorigenesis and disease progression. This theory hypothesizes that a population of the tumor cell with similar functional and phenotypic characteristics as normal tissue stem cells are responsible for formation and advancement of many human cancers. The CSCs subpopulation can differentiate into non-CSC tumor cells and promote phenotypic and functional heterogeneity within the tumor. The presence of CSCs has been reported in a number of human cancers including blood, breast, brain, colon, lung, pancreas prostate and liver. Although the origin of CSCs remains a mystery, recent reports suggest that the phenotypic characteristics of CSCs may be plastic and are influenced by the microenvironment specific for the individual tumor. Such factors unique to each tumor preserve the dynamic balance between CSCs to non-CSCs cell fate, as well as maintain the proper equilibrium. Alternating such equilibrium via dedifferentiation can result in aggressiveness, as CSCs are considered to be more resistant to the conventional cancer treatments of chemotherapy and radiation. Understanding how the tumoral microenvironment affects the plasticity driven CSC niche will be critical for developing a more effective treatment for cancer by eliminating its aggressive and recurring nature that now is believed to be perpetuated by CSCs.

Duplication of TBK1 Stimulates Autophagy in iPSC-derived Retinal Cells from a Patient with Normal Tension Glaucoma.

Abstract: Duplication of theTBK1 gene causes normal tension glaucoma (NTG); however the mechanism by which this copy number variation leads to retinal ganglion cell death is poorly understood. The ability to use skin-derived induced pluripotent stem cells (iPSCs) to investigate the function or dysfunction of a mutant gene product in inaccessible tissues such as the retina now provides us with the ability to interrogate disease pathophysiology in vitro. iPSCs were generated from dermal fibroblasts obtained from a patient with TBK1-associated NTG, via viral transduction of the transcription factors OCT4, SOX2, KLF4, and c-MYC. Retinal progenitor cells and subsequent retinal ganglion cell-like neurons were derived using our previously developed stepwise differentiation protocol. Differentiation to retinal ganglion-like cells was demonstrated via rt-PCR targeted against TUJ1, MAP2, THY1, NF200, ATOH7 and BRN3B and immunohistochemistry targeted against NF200 and ATOH7. Western blot analysis demonstrated that both fibroblasts and retinal ganglion cell-like neurons derived from NTG patients with TBK1 gene duplication have increased levels of LC3-II protein (a key marker of autophagy). Duplication of TBK1 has been previously shown to increase expression of TBK1 and here we demonstrate that the same duplication leads to activation of LC3-II. This suggests that TBK1-associated glaucoma may be caused by dysregulation (over-activation) of this catabolic pathway.

The limitations of QALY: a literature review

Abstract: Introduction: The Quality Adjusted Life Year (QALY) is a recognised metric used to evaluate new and innovative healthcare treatments and optimise resource allocation via rational and explicit methodologies. This review examines present limitations of the QALY metric and foreseeable challenges linked to the advancement of regenerative medicine. Methods: The extant literature was reviewed through electronic searches of four key databases; namely Medline, EMBASE, Econlit and Cochrane. Manuscripts were selected according to pre-determined inclusion criteria. Results: Three common themes emerged concerning the limitations of QALYs. These were ethical considerations, methodological issues and theoretical assumptions and context or disease specific considerations.