A new model of crystal growth is presented that describes the phenomena on atomic length and diffusive time scales. The former incorporates elastic and plastic deformation in a natural manner, and the latter enables access to time scales much larger than conventional atomic methods. The model is shown to be consistent with the predictions of Read and Shockley for grain boundary energy, and Matthews and Blakeslee for misfit dislocations in epitaxial growth. DOI: 10.1103/PhysRevLett.88.245701 PACS numbers: 64.60.Cn, 05.70.Ln, 64.60.My, 81.30.Hd The appearance and growth of crystal phases occurs in many technologically important processes including epitaxial growth and zone refinement. While a plethora of models have been constructed to examine various aspects of these phenomena, it has proven difficult to develop a computationally efficient model that can be used for a wide range of applications. For example, standard molecular dynamics simulations include the necessary physics but are limited by atomic sizes (Å) and phonon time scales (ps). Conversely, continuum field theories can access longer length (i.e., correlation length) and time (i.e., diffusive) scales, but are difficult to incorporate with the appropriate physics. In this paper a new model is presented that includes the essential physics and is not limited by atomic time scales.To illustrate the features that must be incorporated, it is useful to consider two examples. First, consider the nucleation and growth of crystals from a pure supercooled liquid or vapor phase. In such a process, small crystallites nucleate (heterogeneously or homogeneously) and grow in arbitrary locations and orientations. Eventually, the crystallites impinge on one another and grain boundaries are formed. Further growth is then determined by the evolution of grain boundaries. Now consider the growth of a thin crystal film on a substrate of a different crystal structure. The substrate stresses the overlying film which can destabilize the growing film and cause an elastic defect-free morphological deformation [1,2], plastic deformation involving misfit dislocations [3], or a combination of both. Thus, the model must be able to nucleate crystallites at arbitrary locations and orientations and contain elastic and plastic deformations. While all these features are naturally incorporated in atomistic descriptions, they are much more difficult to include in continuum or phase field models.Historically, many continuum models have been developed to describe certain aspects of crystal growth and liquid/solid transitions in general. At the simplest level, "model A" in the Halperin and Hohenberg [4] classification scheme has been used to describe liquid/solid transitions. This model treats all solids equivalently and does not introduce any crystal anisotropy. Extensions to this basic model have been developed to incorporate a solid phase that has multiple states that represent multiple orientations [5,6] or, recently [7], an infinite number of orientations. Unfortunately, these models ...

Multipotent mesenchymal stromal cells (MSCs) have potential therapeutic benefit for the treatment of neurological diseases and injury. MSCs interact with and alter brain parenchymal cells by direct cell-cell communication and/or by indirect secretion of factors and thereby promote functional recovery. In this study, we found that MSC treatment of rats subjected to middle cerebral artery occlusion (MCAo) significantly increased microRNA 133b (miR-133b) level in the ipsilateral hemisphere. In vitro, miR-133b levels in MSCs and in their exosomes increased after MSCs were exposed to ipsilateral ischemic tissue extracts from rats subjected to MCAo. miR-133b levels were also increased in primary cultured neurons and astrocytes treated with the exosome-enriched fractions released from these MSCs. Knockdown of miR-133b in MSCs confirmed that the increased miR-133b level in astrocytes is attributed to their transfer from MSCs. Further verification of this exosome-mediated intercellular communication was performed using a cel-miR-67 luciferase reporter system and an MSC-astrocyte coculture model. Cel-miR-67 in MSCs was transferred to astrocytes via exosomes between 50 and 100 nm in diameter. Our data suggest that the cel-miR-67 released from MSCs was primarily contained in exosomes. A gap junction intercellular communication inhibitor arrested the exosomal microRNA communication by inhibiting exosome release. Cultured neurons treated with exosome-enriched fractions from MSCs exposed to 72 hours post-MCAo brain extracts significantly increased the neurite branch number and total neurite length. This study provides the first demonstration that MSCs communicate with brain parenchymal cells and may regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes.

Neurologic benefit resulting from hMSC treatment of stroke in rats may derive from the increase of growth factors in the ischemic tissue, the reduction of apoptosis in the penumbral zone of the lesion, and the proliferation of endogenous cells in the subventricular zone.

Object Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). Here, we test a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. Methods Wistar rats were subjected to TBI followed by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle phosphate-buffered saline (n = 8/group) 24 hours later. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, neurological severity score and footfault tests were performed. Animals were sacrificed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Results Compared with saline-treated controls, exosome-treated TBI rats showed significant improvement in spatial learning at 34-35 days measured by the Morris water maze test (p < 0.05), and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatment significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn immature and mature neurons in the dentate gyrus as well as reduced neuroinflammation. Conclusions We, for the first time, demonstrate that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly other neurological diseases.

Exosomes are 30–150 nm vesicles secreted by a wide range of mammalian cells that can contain microRNA (miRNA). To test if marrow stromal cell (MSC) exosomes could be used as a vehicle for delivery of anti-tumor miRNAs, we transfected MSCs with a miR-146b expression plasmid, and harvested exosomes released by the MSCs. Intra-tumor injection of exosomes derived from miR-146-expressing MSCs significantly reduced glioma xenograft growth in a rat model of primary brain tumor.

The present study investigates the induction of neurogenesis, reduction of apoptosis, and promotion of basic fibroblast growth factor (bFGF) expression as possible mechanisms by which treatment of stroke with bone marrow stromal cells (MSCs) improves neurological functional recovery. Additionally, for the first time, we treated cerebral ischemia in female rats with intraveneous administration of MSCs. Female rats were subjected to 2 hr of middle cerebral artery occlusion (MCAo), followed by an injection of 3 x 10(6) male (for Y chromosome labeling) rat MSCs or phosphate-buffered saline (PBS) into the tail vein 24 hr after MCAo. All animals received daily injection of bromodeoxyuridine (BrdU; 50 mg/kg, i.p.) for 13 days after treatment for identification of newly synthesized DNA. Animals were sacrificed at 14 days after MCAo. Behavioral tests (rotarod and adhesive-removal tests) were performed. In situ hybridization, immunohistochemistry, and terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) were performed to identify transplanted MSCs (Y chromosome), BrdU, bFGF, and apoptotic cells in the brain. Significant recovery of behavior was found in MSC-treated rats at 7 days in the somatosensory test and at 14 days in the motor test after MCAo compared with control, PBS-treated animals (P<.05). MSCs were found to survive and preferentially localize to the ipsilateral ischemic hemisphere. Significantly more BrdU-positive cells were located in the subventricular zone (P<.05), and significantly fewer apoptotic cells and more bFGF immunoreactive cell were found in the ischemic boundary area (P<.05) of MSC-treated rats than in PBS-treated animals. Here we demonstrate that intravenously administered male MSCs increase bFGF expression, reduce apoptosis, promote endogenous cellular proliferation, and improve functional recovery after stroke in female rats.

We demonstrate that the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and simvastatin enhance functional outcome and induce brain plasticity when administered after stroke to rats. With atorvastatin treatment initiated 1 day after stroke, animals exhibited significant increases in vascular endothelial growth factor, cyclic guanosine monophosphate, angiogenesis, endogenous cell proliferation and neurogenesis, and an increase in the synaptic protein, synaptophysin. Atorvastatin-induced angiogenesis in a tube formation assay was reduced by an antibody against the vascular endothelial growth factor receptor 2 (FIK-1) and by the nitric oxide synthase inhibitor, N-mono-methyl-L-arginine (L-NAME). Atorvastatin also induced phosphorylation of Akt and Erk in cultured primary cortical neurons. These data indicate that atorvastatin induced brain plasticity and has neurorestorative activity after experimental stroke.

Background and Purpose Multipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis and axonal outgrowth. We therefore investigated whether the miR-17-92 cluster enriched exosomes (Exo-miR-17-92+) harvested from MSCs transfected with a miR-17-92 cluster plasmid enhance neurological recovery compared to control MSC derived exosomes (Exo-Con). Methods Rats subjected to 2 hours of transient middle cerebral artery occlusion (MCAO) were intravenously administered Exo-miR-17-92+, Exo-Con, or liposomes, and were sacrificed 28 days post MCAO. Histochemistry, immunohistochemistry and Golgi-Cox staining were used to assess dendritic, axonal, synaptic and myelin remodeling. Expression of phosphatase and tensin homolog (PTEN) and activation of its downstream proteins, protein kinase B (PKB or Akt), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase 3 beta (GSK-3β) in the peri-infarct region were measured by means of Western blots. Results Compared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery, but Ex-miR-17-92+ treatment had significantly more robust effects on improvement of neurological function, and enhancements of oligodendrogenesis, neurogenesis and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the Ex-Con treatment. Moreover, Ex-miR-17-92+ treatment substantially inhibited PTEN, a validated miR-17-92 cluster target gene, and subsequently increased the phosphorylation of PTEN downstream proteins, Akt, mTOR and GSK-3β compared to Ex-Con treatment. Conclusions Our data suggest that treatment of stroke with tailored exosomes enriched with the miR-17-92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting PTEN to activate the PI3K/Akt/mTOR/GSK-3β signaling pathway.