In the July 8th issue of Cell Stem Cell, M. Mohrin et al. from the Univ. of Calif., San Francisco reported their study results on quiescent hematopoietic stem cells (HSCs) being double-edged sword. The investigators noted that in active proliferating HSCs there exist a protective mechanism for maintaining the stem cell niche by minimizing endogenous stress resulting from cellular respiration and DNA replication. The experimental results revealed that HSCs have unique intrinsic mechanism for protecting the stem cell compartment in which proliferating HSCs exposed to ionizing irradiation results in upregulation of prosurvival gene expression, activation of p53 in response to DNA damage, and subsequent apoptosis. However, the researchers found that in quiescent HSCs the DNA repair mechanism in response to ionizing irradiation is mediated by nonhomologous end joining (NHEJ) resulting in genomic rearrangement and hematopoietic abnormalities. Thus, the authors concluded that quiescent HSCs are intrinsically vulnerable to mutagenesis following DNA damage.

The longevity and the plasticity of aging appears to be controlled by epigenetic modification of chromatin. It also has been suggested that aging is associated with depletion and deterioration of the stem cell compartment within various tissues and organs of the body. In the June 16th online edition of Nature, scientists from Stanford University, E. L. Green et al., published their study on the relationship between histone methylation and longevity in round worms (C. elegans). The researchers noted that histone methylation is critically important in maintaining stem cell pluripotency in mammals, but not much is known regarding the mechanisms of methylation and aging. From their experimental results, the investigators identified ASH-2 tithorax complex as a key regulator of lifespan in C. elegans due to trimethylation of histone H3 at lysine 4 (H3K4). Additionally, the results revealed that deficiencies in members of the ASH-2 complex (either ASH-2, WDR-5, or methyltranferase SET-2) extended worm lifespan. It was also shown that H3K4 demethylase RBR-2 is required for normal lifespan, which supports the thesis that "excess H3K4 trimethylation is detrimental for longevity." Life extension by ASH-2 complex deficiencies also required an intact adult germline and the continuous production of mature eggs. The authors concluded from their experimental data that "ASH-2 and RBR-2 act in their germline, at least in part, to regulate lifespan and to control as sent of genes involved in lifespan determination." (It may also suggest that these complexes may also modulate the stem cell compartments in the worm?).

In a study published in the May 30th online edition of Nature, R. K. Chodavarapu et al. from Univ. of California, Los Angeles published the results of their study on nucleosomes and DNA methylation patterns and their effects on gene expression. The investigators used genome-wide nucleosome positioning analysis of Arabidopsis thaliana (mustard weed) for studying DNA methylation as model for gene regulation in human stem cells. The researchers noted that "changes in DNA methylation are behind a lot of what makes a stem cell a stem cell," particularly, with respect to regulating stem cell differentiation. The experimental results revealed that nucleosomal DNA were highly methylated compared to flanking DNA. This observation suggests that DNA methytranferases preferentially targets nucleosome-bound DNA. This methylation pattern was also observed in human stem cells which suggests that DNA methyltransferase targeting of the nucleosome-bound DNA is a highly conserved evolutionary process. The single base resolution analysis data also demonstrated highly enriched exons in the nucleosomes at the intron-exon and exon-intron boundaries. Additionally, RNA polymerase II (Pol II) are highly enriched on exons relative to the introns, which the authors construe as supporting the hypothesis that nucleosomes positioning regulates the processing of Pol II.

South Korean scientists, J. S. Lee et al., from Ajou Univ. School of Medicine (Suwon) reported in the April 19th online edition of Stem Cells their study results of a clinical trial in which ischemic stroke patients were treated with autologous bone marrow-derived mesenchymal stem cells (MSCs). The five years clinical trial consisted of 52 patients with severe middle cerebral artery infarct. In random, open-labeled, observer-blinded study, ex vivo expanded autologous MSCs were administered intravenously into 16 patients and 36 patients served as the control group. After 5 years of follow up, the investigators found that 25% of the MSC group and 58.3% died during the follow-up period. There were no significant side effects reported for MSC treatment. The study revealed that co-morbidities such as seizures and recurrent vascular episodes did not differ between the two groups. The researchers noted that clinical improvement for the MSC group was associated with increased plasma levels of stromal cell-derived factor-1 (SDF-1). The authors concluded that autologous MSC transplantations were safe for stroke patients and that "the therapy may improve recovery after stroke depending on the specific characteristics of the patients."

In today's (April 8th) online edition of the J. of Translational Medicine, N. A. Mikirova et al. from the Bio-communications Research Institute (Wichita, Kansas) reported their study results in increasing the number of circulating hematopoietic (CD34+ CD133+) and endolthelial (KDR+) progenitor cells in the peripheral blood. The investigators used a nutritional supplement consisting of a cocktail containing green tea, astralagus, goji berry extracts, Lactobacillus fementum, ellagic acid, beta 1,3 glucan and vitamin D3 in 18 adult human subjects (20-72 years old). The subjects ingested 2 capsules twice daily and the their were analyzed on days 1, 2, 7, and 14. The study results revealed that there were an increase of 90.35% of CD133 cells and 53.13% of CD34 cells after 2 days of supplement ingestions as well as a 95.35% increase in endolthelial progenitors on day 7 of continuous supplement ingestion. The authors concluded that nutriceutical supplements may be a useful stimulator of the "reparative processes associated with mobilization of hematopoietic and endolthelial progenitors."

In the March 3rd online edition of Nature, S. A. Saenz et al. from the University of Pennsylvania published a their study on cytokine, IL25, which appears to be a growth factor for eliciting a subpopulation of multipotent progenitor (MPP) cells whose progenies promote a Th2-dependent immune response. The investigators found that IL25 is a member of the IL17 cytokine family that promotes a lineage-negative (Lin-) MPP cell population which accumulates in the lymphoid tissues of the gut. This non-hematopoietic cell-derived cytokine appears to induce an innate immune response to gastrointestinal parasitic infections such as helminths. These MPP cells were found to be multipotent in their ability to differentiate into monocyte/macrophage and granulocyte lineages both in vitro and in vivo. These MPP cells that could generate a Th2 cytokine response expressed Sca-1 and of c-Kit (intermediate expression). Progenies of the MPP cells were found to be competent antigen-presenting cells in adoptive transfer experiments. For example MPP(Th2) cells conferred protective immunity against helminth infections in susceptible IL25 -/- mice. The authors concluded that "the ability of IL25 to induce the emergence of an MPP(type2) cell population identifies a link between the IL17 cytokie family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes Th2 cytokine responses at mucosal sites."

In a study conducted by A. R. Cohen et al. from the University of Wisconsin, the investigators reported in the February 7th issue of Nature Methods a computational method for predicting stem cell fates. A major challenge of stem cell biologists is trying to determine the fate of stem cells grown in cultures. Since cells grown in vitro look alike, it is very difficult to determine the characteristics of the daughter cells following mitosis/asymmetrical cell division. The researchers developed a computational method using algorithms which predicted cell division outcomes based upon shapes and movement of the cells. With retinal progenitor cells (RPCs), the investigators were able to predict with 99% accuracy "whether the RPCs will undergo a self-renewing or terminal i." Additionally, this computational method was able to predict with 87% accuracy whether post-mitotic cell division of the RPCs produce two cells expressing photoreceptors or another combination of offspring. The experimental results also showed that the computer could track and generate predictions for 40 cells simultaneously. The authors concluded that their "method could be used to isolate cell populations with specific developmental potential."

One of the hallmarks for pluripotency in human stem cells is the presence of hTERT (human telomerase reverse transcriptase) which is an enzyme for synthesizing and adding telomeres to the ends of chromosomes. The presence of hTERT provides the self-renewing properties of pluripotent stem cells. Additionally, somatic cells' telomeres shorten as the cells divide and age. Thus, telomere length is considered a marker for biological aging. In a study published in the February 7th online edition of Nature Genetics, V. Codd et al. from the University of Leicester (UK) the results of their analysis of leukocyte telomere length in 2,917 individuals and aging. The investigators conducted a genome-wide association analysis between telomere length on 3q26 (rs12696304) region and the locus hTERC encoding telomerase RNA. The researchers found that "each copy of the minor allelle of rs126936304 was associated with approximately 75 base-pair reduction in mean telomere length (which was) equivalent to ~3.6 years of age-related telomere-length attrition." (There have been anti-aging proponents who recommend ingesting nutritional supplements rich in anti-oxidants which they believe can indirectly slow down the aging process by reducing generation of reactive oxygen species driving somatic cellls into apoptosis. However, it would be interesting to conduct a study reinfusion of autologous adult stem cells would impact the aging process.)

In the November 4th online edition of Stem Cells, K. Zhao et al. from Rutgers University reported their study results on Th1 cells regulating hematopoietic progenitor cell (HPC) homeostasis. The investigators found that products from Th1 but not Th2 cells caused rapid expansion of HPCs with surface markers of lineage^low,Sca-1+,C-kit+ (LSK) in vivo and in vitro. Interferon-gamma (IFNγ) particularly was found to upregulate expression of Sca-1 in lineage^low,Sca-1-,C-kit+ cells. It was found that activating expression of Sca-1 was dependent on IFNγR1 signaling and the STAT1 pathway. IFNγ-induced LSK cells had a higher proliferative potential than control LSK cells and had a biased toward differentiation of myeloid lineages. The authors concluded that their study results suggest "a novel role of IFNγ in activating hematopoietic progenitor cells and provide new insight into the clinical application of interferon."

Dutch scientists c. Robin et al. from Erasmus University Medical Center reported in the October 2nd issue of Cell Stem Cells results of their study on hematopoietic stem cell (HSC) niche in the placenta during human embryogenesis. The investigators noted that in mice and humans HSCs are initially produced in the aorta-gonad-mesonephros region of the embryo. However, very little is known about other anatomical sites that contain HSCs or progenitors during human development. The study data revealed that a HSC niche is supported by human placenta from midgestation to term during fetal development. Additionally, the researchers were able to generate stromal cell lines isolated from the placenta at different developmental time points. The stromal cells were reported as pericyte-like cells which "support human hematopoiesis." Immunohistochemistry analysis demonstrated that HSCs are located in regions of the placenta containing pericyte/perivascular cells. The authors concluded that the "human placenta is a potent hematopoietic niche throughout development."