In the July 23rd issue of the Journal of Neuroscience, G. Lewandowski & O. Steward from the University of California, Irvine reported their study results on regenerating corticospinal axons after spinal cord injury (SCI). The investigators used a gene therapy approach by injecting intracortically into rats adeno-associated virus as a vector carrying the gene encoding for shRNA (AAVsh) which inhibits the expression of phosphatase and tensin homolog (PTEN/AAVshPTEN). Rats receiving AAVshPTEN alone were found not to exhibit improved motor function following cervical dorsal hemisection injuries (SCI) 10 weeks after the injury. However, the group receiving AAVshPTEN concomitant with injection of salmon fibrin at the injury site were shown to have improved motor function with significantly higher forelimb-reaching scores. Additionally, the group receiving AAVshPTEn and salmon fibrin had axons extending further caudally in the corticospinal tract (CST) than the controls or group receiving only AAVshPTEN. The authors concluded from their study observations that their "data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly improve voluntary motor function after SCI by enabling regenerative growth of CST axons."
In the June 5th online early publication of Medicine & Science in Sports & Exercise, K. Zou et al. from the University of Illinois reported their study results on mesenchymal stems rejuvenating skeletal muscle after resistance exercise in mice. The investigators had found that transgenic (Tg) mice overexpressing the transmembrane protein α7B integrin enhanced satellite cell and growth response to eccentric exercise. Muscle mesenchymal stem cells (mMSCs/Sca1+CD45-) isolated from α7Tg mice were dye-labeled and injected into skeletal muscle of wild type recipient mice. Post-injection the mice were either sedentary or subjected to eccentric exercise training (downhill running) on a treadmill 3X/week. The experimental results demonstrated that mMSCs did not directly fuse with existing muscle fiber but enhanced Pax7+ cell numbers and myonuclear content in existing muscle fibers in the group undergoing eccentric exercise training. Also, rip strength improved in the exercise group. However, mMSC transplantation did not enhance tissue repair and growth in the absence of exercise. The authors concluded from their study that "mMSCs contribute to beneficial changes in satellite cell expansion and growth in α7Tg muscle following eccentric exercise. Thus, MSCs that naturally accumulate in muscle following eccentric contractions may enhance the adaptive response to exercise."
In the April 22nd online advance publication of Cell Transplantation, S. Dhingra et al. from the University of Toronto published their study results on transduction of allogeneic smooth muscle cells (SMCs) with Interleukin -10 (IL-10) gene to enhance engraftment in a rat model with experimental-induced myocardial infarction. The investigators used three groups of rats injected into the infarct site with either unmodified autologous, unmodified allogeneic, or allogeneic smooth muscle cells transduced with IL-10 gene. In vitro and in vivo results demonstrated that SMCs expressing IL-10 increased the number of regulatory T cells (CD4+CD25+) and reduced the number of cytotoxic T cells (CD8+) concomitant with a reduction in the anti-allogeneic antibody response. Transplantation of both unmodified autologous SMCs and modified allogeneic SMCs were shown to improve ventricular function (fractional shortening) and left ventricular dimensions (wall thickness) compared to the control or unmodified allogeneic SMCs. The researchers also reported enhanced survival in the groups receiving unmodified autologous SMCs and modified allogeneic SMCs. The authors concluded from their study observations "that IL-10 gene therapy with allogeneic SMCs prevents detrimental allo-immune response in the recipient, thereby increasing the survival of transplanted allogeneic SMCs and more effectively restoring cardiac function."
In the July 10th online advance publication of Cell Stem Cell, K. N. Cosgun et al. from TU Dresden Faculty of Medicine (Dresden, Germany) reported their study results in developing a mouse strain as an animal model for analyzing engraftment of transplanted human hematopoietic stem cells (HSCs). The investigators developed immune-deficient mouse strains containing Kit mutations. Human HSCs were found to engraft efficiently in the Kit mutant mice without irradiation conditioning. The researchers reported that mutation of the Kit receptor "enables robust, uniform, sustained, and serially transplantable engraftment of human HSC in adult mice. Additionally, human HSCs demonstrated robust multilineage engraftment and self renewal in the mutant mice. Differential Kit expression resulted in identifying two functionally distinct subpopulations of human HSCs. The authors concluded that Kit mutations "open up stem cell niches across species barriers" which may have a significant potential and broad application in human HSC research.
In the July 3rd online early publication of Stem Cells, N. van Gastel et al. from KU Lueven (Lueven, Belgium) published their experimental results on ex vivo expansion of murine periosteal cells in the presence FGF2 can give rise to mature bone post-implantation into a bone defect. The investigators found that enhanced endochondral ossification of FGF2-primed cells is driven by increased production of bone morphogenetic protein 2 (BMP2). This phenomenon appears to be exclusive for periosteal cells since FGF2-primed bone marrow stromal cells form less bone and progress "exclusively through the intramembranous pathway, revealing essential differences between both cell pools." The authors concluded from their study results that their "findings provide insight in the molecular regulation of fracture repair by identifying an unique interaction between periosteal cells and FGF2."
In the July 3rd online advanced publication of Stem Cells, X. Hu et al. from Zhejiang University College of Medicine published their study results on the underlying mechanism in which hypoxia augments the protective and therapeutic effects of mesenchymal stem cells (MSCs). The investigators found that hypoxia increased survival, mobility, and protection of co-cultured cardiomyocytes with MSCs under hypoxic conditions. These protective effects occurred with increased expression of leptin and the surface receptor CXCR4 in the MSCs. Additionally, knockdown of leptin with shRNA abolished the enhanced effect. With MSCs from obese, diabetic and wild type mice, only pretreated hypoxic MSCs from wild type mice were able to exhibit their protective effect in a mouse model of myocardial infarction. Hypoxia pretreatment of the MSCs also enhanced engraftment, recruitment of c-Kit+ cells to the infarct site, vascular density, reduced infarct size and long-term contractile function. The authors concluded from their study results that "leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs." The researchers also surmised that "leptin may play a physiological role in priming resident MSCs in the bone marrow endosteum" for optimal tissue repair."
In June 23rd online advance issue of PNAS, Y. Rinkevich et al. from Stanford University School of Medicine, reported their study results on the role of nerves in tissue maintenance and regeneration in mammalian hind limb. In Urodeles, surgical denervation prior to limb amputation resulted in regeneration failure. The investigators used genetic lineage tracing and clonal analyses of individual cells in mouse hind limb tissues devoid of nerves supplying the digit tip during regeneration. The experimental results revealed normal cellular turnover, replacement, and cellular differentiation from tissue stem/progenitor cells. However, the digit tips displayed patterning defects in both bone and nail matrix which mimic clinical observations of patients with nerve damage resulting from spinal cord injury. The authors concluded their experimental observations can provide significant insight into understanding the effects of nerves on "etiologies of human injury."
In the May 22nd online advanced publication of Cell Transplantation, L. Zhou et al. from Sun Yat-sen University (Guangzhou, China) reported their study results on transplanting bone marrow-derived mesenchymal stem cells (MSCs) into animal model of multiple sclerosis (MS). The investigators used ethidium bromide (EB) to induce demyelination of the spinal cord in rats. The MSCs were pre-treated with neurotrophin-3 (NT-3) and retinoic acid (RA) to promote differentiation into oligodendrocyte-like cells. The experimental results showed that both NT-3 and RA increased transcription of tyrosine receptor kinase C (TrkC) mRNA in cultured MSCs (NR-MSCs). Electroacupuncture (EA) was shown to increase NT-3 levels and enhanced differentiation of the oligodendrocyte cells from NR-MSCs transplanted into the demyelinated spinal cord. Grafted NR-MSCs promoted myelin formation and when combined with EA reduced demyelination and induced remyelination. Additionally, cortical motor nerve conduction improved following NR-MSC engraftment. The authors concluded that their data "suggest that pre-induced MSC transplantation combined with EA treatment not only increased MSC differentiation into oligodendrocyte-like cells forming myelin sheaths, but also promoted remyelination and functional improvement in nerve conduction in the demyelinated spinal cord."
In the June 11th advance online publication of Stem Cells, Z. Yang et al. from the Third Military Medical University (Chongqing, China) published their study results on reprogramming mammalian multinucleated skeletal myofibers into proliferating mononucleated cells. The investigators showed that ecotopic expression of the transcription factor Msx1 reprogrammed post-mitotic, multinucleated, primary mouse myotubes into proliferating mononuclear cells. The researchers concluded that reprogramming the cells induced dedifferentiation in which reactivation of genes normally expressed in embryonic muscle progenitor cells resulted in the generation of muscle tissue. Additionally, these reprogrammed cells were observed to "fuse with existing fibers and regenerate myofibers in a time-dependent manner." Transplantation of the "dedifferentiated" cells generated large number of myofibers that over time regenerated the damaged muscle in 12 weeks. The authors concluded from their study results that "mammals can harness muscle regeneration strategy used in lower organisms when the same molecular pathway is activated."
In the June 6th online early publication of Cell Transplantation, H. J. Lee et al. from the Chung-Ang University College of Medicine published their study results on the effect of transplanting mesenchymal stem cells (MSCs) directly into the bladder wall of rats with experimentally induced spinal cord injury (SPI). Four weeks after the onset of SPI, MSCs (B10) labeled with fluorescent magnetic nanoparticles (MNPs) were injected into the bladder wall. Four weeks post transplantation, the investigators observed in bladder fibrosis and bladder function as well as a marked reduction in collagen deposition. Transplanted B10 cells were reported to differentiate into smooth muscle cells. The experimental data also demonstrated B10 cells surviving 4 weeks post transplantation in the bladder. The authors concluded that "transplanted B10 cells inhibited bladder fibrosis and ameliorate bladder dysfunction in rat SCI model." They also concluded that "MSC-based cell transplantation may be a novel therapeutic strategy for bladder dysfunction in patients with SCI."