This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1).

/pdf/neurotoxic-reactive-astrocytes-are-induced-by-activated-33z6oieelb.pdf

Neurotoxic reactive astrocytes are induced by activated microglia

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

/pdf/astrocytes-biology-and-pathology-2hq13zf0bo.pdf

Astrocytes: biology and pathology

Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

Neurotrophins: roles in neuronal development and function.

Mechanisms and functional implications of adult neurogenesis.

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0197

Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.

Mammalian neural stem cells

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoterenhancer (Nes-Stat3 –/– , Nes-Socs3 –/– ). Reactive astrocytes in Nes-Stat3 –/– mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3 –/– mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. Because the regenerative capability of the mammalian CNS is poor, limited functional recovery occurs during the chronic phase of SCI. At the subacute phase of SCI, however, gradual functional recovery is observed to some extent in both rodents and humans (except in cases of complete paralysis). The mechanism behind this functional recovery remains unclear. Here, we investigated this issue by focusing on the action of reactive astrocytes in a mouse model of SCI. To interpret the process of paralysis improvement in the subacute phase, we examined serial histological sections of contused spinal cords and followed motor function for 6 weeks after injury in wild-type mice and found that the area of neural cell loss gradually enlarged in a rostral-caudal direction within a few days after SCI (acute phase) and a portion of Hu-expressing neurons were positive for cleaved caspase-3, indicating that the secondary injury process lasted for several days in this model (Supplementary Fig. 1 online) during which we observed limited functional recovery (Fig. 1a). Astrocytes surrounding the lesion underwent a typical change of hypertrophy, process extension and increased expression of intermediate filaments such as GFAP and Nestin by 7 d after SCI (Fig. 1b), characteristic of ‘reactive astrocytes.’ Notably, these astrocytes eventually migrated centripetally to the lesion

/pdf/conditional-ablation-of-stat3-or-socs3-discloses-a-dual-role-2kj28keqqx.pdf

Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury.

Recent studies have shown that neurogenesis is enhanced after hypoxia and that erythropoietin (EPO), an inducible cytokine, is produced in the brain as part of the intrinsic hypoxia response. Thus, we asked whether EPO might regulate neurogenesis by forebrain neural stem cells (NSCs). We found that EPO receptors are expressed in the embryonic germinal zone during neurogenesis as well as in the adult subventricular zone, which continues to generate neurons throughout adulthood. Cultured NSCs exposed to a modest hypoxia produced two- to threefold more neurons, which was associated with an elevation in EPO gene expression. The enhanced neuron production attributable to hypoxia was mimicked by EPO and blocked by coadministration of an EPO neutralizing antibody. EPO appears to act directly on NSCs, promoting the production of neuronal progenitors at the expense of multipotent progenitors. EPO infusion into the adult lateral ventricles resulted in a decrease in the numbers of NSCs in the subventricular zone, an increase in newly generated cells migrating to the olfactory bulb, and an increase in new olfactory bulb interneurons. Infusion of anti-EPO antibodies had the opposite effect: an increase in the number of NSCs in the subventricular zone and a decrease in the number of newly generated cells migrating to the bulb. These findings suggest that EPO is an autocrine-paracrine factor, capable of regulating the production of neuronal progenitor cells by forebrain NSCs.

https://www.jneurosci.org/content/jneuro/21/24/9733.full.pdf

Erythropoietin Regulates the In Vitro and In Vivo Production of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells

Embryonic stem (ES) cells are a promising source of cardiomyocytes, but clinical application of ES cells has been hindered by the lack of reliable selective differentiation methods. Differentiation into any lineage is partly dependent on the regulatory mechanisms of normal early development. Although several signals, including bone morphogenetic protein (BMP), Wnt and FGF, are involved in heart development, scarce evidence is available about the exact signals that mediate cardiomyocyte differentiation. While investigating the involvement of BMP signaling in early heart formation in the mouse, we found that the BMP antagonist Noggin is transiently but strongly expressed in the heart-forming region during gastrulation and acts at the level of induction of mesendoderm to establish conditions conducive to cardiogenesis. We applied this finding to develop an effective protocol for obtaining cardiomyocytes from mouse ES cells by inhibition of BMP signaling.

/pdf/transient-inhibition-of-bmp-signaling-by-noggin-induces-14t78m1xig.pdf

Takuya Shimazaki

Papers

Mammalian neural stem cells

Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury.

Erythropoietin Regulates the In Vitro and In Vivo Production of Neuronal Progenitors by Mammalian Forebrain Neural Stem Cells

Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells.

Retinoic-acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells