In the July 8th issue of Stem Cell Research & Therapy, M. J. Mienaltowski et al. from the University of South Florida, Morsani College of Medicine published their study results on the tenogenic properties of progenitor cells derived from either the tendon proper or peritenon of the Achilles tendon. The investigators cultured the isolated progenitors on fibrinogen/thrombin gel-based constructs supplement with recombinant growth/differentiation factor-5 (GDF5). The experimental results demonstrated that the tendon proper-derived progenitors gave rise to a more tendon-like phenotype than the peritenon-derived progenitors. The tendon differentiation markers Scx and Tnmd are expressed at higher levels in tendon proper progenitors than peritenon progenitors. Additionally, transcript levels for Dcn and collagen gene expression (Col12a1 and Col14a1) levels were higher in tendon proper progenitors than in peritenon-derivef progenitiors. The authors concluded that their "findings suggest that progenitors in and around the Achilles tendon posses unique tenogenic differentiation characteristics. Distinctions found in tenogenic differentiation and matrix assembly potentials between these progenitor pools provide insight into possible individual and interactive roles of multiple intrinsic and extrinsic cell populations during tendon repair."
In the August 5th publication of Stem Cell Research & Therapy, A. LluciÓ-Valldeperas et al. from the Health Science Research Institute Germans Triasi Pujol (Barcelona, Spain) reported their study results on the effects of electrical stimulation of cardiomyocyte progenitor cells (CMPCs). The investigators used CMPCs isolated from the adult human atrial appendages which were exposed to a pulsed electrical field for 7 and 14 days (2-ms ef 25mV/cm at 1 Hz alternating current). The experimental results revealed that electrical stimulation modulated CMPC genes and protein expression. The data revealed GATA binding protein 4 (GATA4a) and myocyte enhancer factor 2A (MEF2A) are upregulated. Additionally, cardioregeneration potential of CMPCs improves with electrical stimulation. The authors concluded from their study results that "electrostimulated CMPCs may be best-equipped cells for myocardial integration after implantation."
In the August 11th online early publication of Stem Cells, S. Forostyak et al. from the Academy of Science of the Czech Republic reported their study results on transplanting human bone marrow mesenchymal stromal cells (MSCs) in a rodent model of amyotrophic lateral sclerosis (ALS). The investigators used superoxide dismutase 1 (SOD1) rats for studying changes in the ventral horn perineuronal nets (PNN) following intrathecal administration of the MSCs. In SOD1 rats, it was found that they had abnormal disorganized PNN structure around the spinal motorneurons having a different gene expression profile for Versican, Hapln1, Neurocan, and Tenascin-R. Transplantation of MSCs preserved PNN structure concomitant with enhanced survival of motorneurons. Additionally, the experimental results revealed higher levels of IL-1a and MCP-1 in the cerebral spinal fluid (CSF) of SOD1 rats. The researchers believed changes in cytokine levels in the CSF could serve as biological markers for prognosis, diagnosis, and assessing treatment efficacy for ALS. The authors concluded from their experimental observations that "The administration of human MSCs is a safe procedure that delays the loss of motor function and increases the overall survival of symptomatic ALS animals, by remodeling the recipients' pattern of gene expression and having neuroprotective and immunomodulatory effects."
In the August 6th advance online publication of Nature, L. Pan et al. from the Stowers Institute for Medical Research (Kansas City, MO) reported their study results on the intrinsic factors which determine stem cell self-renewal and differentiation. The investigators used Drosophila melanogaster ovaries to determine the mechanism in which germline stem cells (GSCs) switch from a state of self-renewal to differentiation. The experimental results revealed that the differentiation factor, Bam, controls the functional switch of the COP9 complex from self-renewal to differentiation by way of protein competition. The COP9 complex consists of eight Csn subunits and the complex is required intrinsically for GSC self-renewal. It was noted that other Csn proteins are required for GSC progeny differentiation, with the exception of Csn4. Bam was found to mediate Csn4 sequestration from the COP9 complex via protein competition and inactivates the self-renewing function of COP9 concomitant with other Csn proteins promoting GSC differentiation. The authors concluded from their experimental results that "protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation" may be an important mechanism in which stem cells in other tissue systems uses as a switch from self-renewal to differentiation.
In the August 10th advance online publication of Nature, A. Viale et al. from the University of Texas MD Anderson Cancer Center reported their study results on a subpopulation of cancer cells from pancreatic ductal adenocarcinoma (PDAC) which survives targeted oncogene-driven signaling pathways. KRAS mutations is known to drive and maintain PDAC. The investigators used an inducible mouse model of mutated Kras to uncover a subpopulation of dormant tumor cells that survived oncogene ablation. The experimental results revealed that the dormant cancer cells are responsible for tumor relapse with a cancer stem cell phenotype. The dat also demonstrated that these subpopulation of cancer cells rely on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of the cancer stem cells revealed expressed genes which regulated mitochondrial function, autophagy and lysosome activity concomitant with a strong reliance on mitochondrial respiration for cellular energetics. The cancer stem cell were highly sensitive to inhibitors of oxidative phosphorylation and prevented tumor recurrence. The authors concluded that their study results "illuminate a therapeutic strategy of combined targeting of KRAS pathway and mitochondrial respiration to manage pancreatic cancer."
In the July 30th online early publication of Cell Transplantation, M. Murakami et al. from the National Center for Geriatrics and Gerontology Research Institute (Obu, Japan) reported their study results on comparing mesenchymal stem cells (MSCs) from different tissue sources in their ability to regenerate dental pulp. The investigators used granulocyte-colony stimulating factor (G-CSF) for mobilizing dental pulp stem cells (MDPSCs), bone marrow stem cells (MBMSCs) and adipose-derived stem cells (MADSCs) from a dog. The experimental results demonstrated that the trophic effects of MDPSCs on angiogenesis, neurite extension, and migration were higher than with MBMSCs or MADSCs. Transplantation of MDPSCs produced higher volume of regenerated pulp concomitant with a higher density of vascularization and innervation than with MBMSCs and MDPSCs. However, the researchers found that collagenous matrix in the pulp had a greater amount of dentin sialophosphoprotein (DSPP) positive odontoblast-like cells when transplanted with MBMSCs (highest) and significantly higher with MADSCs compared to MDPSCs. The authors concluded from their study observations that "an alternative cell source for dental pulp/dentin regeneration are stem cells form bone marrow and adipose tissue."
Category: Reprogramming
In the August 7th online advance publication of Neuron, P. Lu et al. from the University of California, San Diego reported their experimental results on reprogramming human skin cells and differentiating the induced pluripotent stem cells (iPSCs0 into neuronal stem cells (NSCs). The investigators used skin cells from an 86 years old man for generating iPSC-derived neural stem cells which were subsequently grafted into adult immunodeficient rats after spinal cord injury (C5 lateral hemisections). Three months after the graft, the experimental results revealed iPSC-derived NSCs differentiated into axons and extended into the host spinal cord and formed synaptic contacts with rat neurons. Additionally, graft-derived human axons extended throughout the rat central nervous system extending through both the white and gray matter of the brain. The authors concluded that their "findings indicate that intrinsic neuronal mechanisms readily overcome the inhibitory milieu of the adult injured spinal cord to extend many axons over very long distances: these capabilities persist even in neuron reprogrammed from very aged human cells."
In the July 31st issue of Nature, H. Guo et al. from Peking University Third Hospital (Bejing, China) reported in a letter to Nature their study results on profiling the methylome of human early embryos. The investigators found that a major wave of genome-wide demethylation is completed by the 2-cell stage. Demethylation of the paternal genome occurs at a faster rate than the maternal genome. The experimental data revealed that the "inverse correlation between promoter methylation and gene expression gradually strengthens during early embryonic development and peaks at the post-implantation stage." Additionally, in pluripotent human embryonic stem cells (ESCs) trimethylation of histone H3 at lysine 4 (H3K4me3) mark at the promoter regions are devoid of DNA methylation. The scientists also noted that evolutionary young "nuclear elements" are demethylated to a milder extent that older elements in the same family. The authors concluded that their work "provide insights into the critical features of the methylome of human early embryos, as well as its functional relation to the regulation of gene expression and the repression of transposable elements."
In the March 31st issue of Developmental Cell, T. T. Southall et al. from Imperial College of London (UK) published their study results on a mechanism in which the BTB-Zn finger transcription factor, Lola, prevents neurons from dedifferentiating to multipotent, stem cell-like state. The investigators reported that Lola is required to maintain neurons in a differentiated state by repressing neural stem cell genes and cell-cycle genes in postmitotic neurons. The study data revealed that neurons dedifferentiate in lola mutants. Additionally, the dedifferentiated mutant neurons had their neural stem cells genes turned on and subsequently began forming tumors as tumor-initiating cells. The authors concluded that "neurons rather than stem cells or intermediate progenitors are the tumor-initiating cells in lola mutants."
Category: Reprogramming
In the July 38th online early publication of Stem Cells Translational Medicine, D. Sareen et al. from Cedars-Sinai Medical Center (Los Angeles) reported their experimental results on generating human induced pluripotent stem cells (iPSCs) and differentiating the cells in limbal epithelial stem cells (LESCs). The investigators generated iPSCs with non-integrating vectors from human primary limbal epithelial cells. Directed limbal differentiation of the iPSCs was the result of cultivating the cells on a natural substrata which mimicked the native LESC niche and included feederless denuded human amniotic membrane (HAM) and de-epithelialized cells. The parent cells were used in order to enhance limbal cell differentiation from iPSCS through "partial retention of parental epigenetic signatures in iPSCS." When comparing the gene methylation patterns between limbal-derived iPSCs and fibroblast-derived iPSCs, the limbal-derived iPSCs had fewer methylation changes which suggested "retention of epigenetic memory during reprogramming." After 2 weeks in culture, the limbal iPSCs expressed markers that more closely related to the parental cells, while fibroblast-derived iPSCs gene expression profile remained closer to parental fibroblasts. The authors concluded that their experimental data "emphasize the importance of the natural niche and limbal tissue of origin in generating iPSCs as a LESC source with translational potential for LSCD treatment."