MEPO promotes neurogenesis and angiogenesis but suppresses gliogenesis in mice with acute ischemic stroke

So your doctors, stroke hospital and stroke association should followup with human research testing this out. That is the minimum a competent doctor, stroke hospital and stroke association should be doing.  But you already know that nothing will be done unless you do this testing yourself.

 

MEPO promotes neurogenesis and angiogenesis but suppresses gliogenesis in mice with acute ischemic stroke

Author links open overlay panelSi-jiaZhang^ab1Rong-liangWang^ab1Hai-pingZhao^abcZhenTao^abJin-chengLi^dFeiJu^abZi-pingHan^abcQing-fengMa^aPingLiu^aShu-beiMa^aGuo-dongCao^efYu-minLuo^abc

https://doi.org/10.1016/j.ejphar.2019.01.066Get rights and content

Abstract

Previously study has proved the non-erythropoietic mutant erythropoietin (MEPO) exerted neuroprotective effects against ischemic cerebral injury, with an efficacy similar to that of wild-type EPO. This study investigates its effects on neurogenesis, angiogenesis, and gliogenesis in cerebral ischemic mice. Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and reperfusion. EPO (5000 U/kg), MEPO (5000 U/kg) or equal volume of normal saline was injected intraperitoneally. Neurological function was evaluated by Rota-rod test, Neurological severity scores (NSS) and Adhesive removal test. After ischemia and reperfusion (I/R), the survival rate, brain tissue loss, neurogenesis, angiogenesis and gliogenesis were detected by Nissl staining, Immunofluorescence and Western blot, respectively. The results shown that MEPO significantly increased survival rate, reduced brain tissue loss, and improved neurological function after MCAO (P<0.05). Furthermore, MEPO obviously enhanced the proliferation of neuronal precursors (DCX) and promoted its differentiation into mature neurons (NeuN) (P<0.05). In addition, compared to normal saline treatment mice, MEPO increased the number of BrdU-positive cells in the cerebral vasculature (P<0.05). Whereas, MEPO treatment also reduced the numbers of newly generated astrocytes (GFAP) and microglia (Iba1) (P<0.05). Among all the tests in this study, there was no significant difference between EPO group and MEPO group. Taken together, MEPO promoted the regeneration of neurons and blood vessels in peripheral area of infarction, and suppressed the gliogenesis, thus promoting neurogenesis, improving neurological function and survival rate. Our findings suggest that the MEPO may be a therapeutic drug for ischemic stroke intervention.

Abstract 141: The Microrna 17-92 Cluster in Neural Progenitor Cells is Required for Stroke-induced Neurogenesis and Gliogenesis

What will your doctor do with this to help your 100% recovery? ANYTHING AT ALL? Or is your incompetent doctor waiting for  SOMEONE ELSE TO SOLVE THE PROBLEM?

 Abstract 141: The Microrna 17-92 Cluster in Neural Progenitor Cells is Required for Stroke-induced Neurogenesis and Gliogenesis

Wanlong Pan, Xianshuang Liu, Xiaoming Zhang, Xinli Wang, Jiani Hu, Ruilan Zhang, Michael Chopp, Zheng Gang Zhang

Stroke. 2017;48:A141

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Abstract

Background: Molecular mechanisms underlying stroke-induced neurogenesis have not been fully investigated. The microRNA 17-92 cluster (miR17-92) regulates proliferation and differentiation of adult neural progenitor cells (NPCs). The present study investigated whether the miR17-92 cluster in NPCs is required for stroke-induced neurogenesis.

Methods and Results: Mice with inducible and conditional knockdown of the miR17-92 cluster in nestin lineage NPCs (nestin-CreER^T2/miR17-92^-/-, 17-92-cKO, n=9) and wild-type litters (WT, n=9) were treated by tamoxifen. Administration of tamoxifen resulted in more than 60% reduction of individual members of the miR-17-92 cluster (miR-17: 1.0 vs 0.4; miR-19a: 1.0 vs 0.3; miR-19b: 1.0 vs 0.2; miR-20a: 1.0 vs 0.4; miR-92a: 1.0 vs 0.4 fold in WT, p<0.05) in NPCs localized to the subventricular zone (SVZ). Two days after termination of tamoxifen treatment, these mice were subjected to permanent right middle cerebral artery occlusion (MCAO) and sacrificed 28 days post-MCAo. Compared to WT mice, 17-92-cKO mice exhibited significant (p<0.05) reduction of proliferation of NPCs measured by the number of Ki67⁺ cells (226±43 vs 471±100 cells/mm²) and the number of DCX⁺ neuroblasts (11±2% vs 24±4% ) in the ischemic SVZ. Cultured NPCs harvested from ischemic cKO mice showed significant (p<0.05) reduction of BrdU⁺ cells (37±2% vs 61±4% WT , n=3/group), Tuj1⁺ neuroblasts (5±0.2% vs 9±0.4% ), GFAP⁺ cells (33±3% vs 53±2% ), and NG2⁺ oligodendrocyte progenitor cells (OPCs, 3±0.1% vs 5±0.5%). These in vivo and in vitro data indicate that reduction of the miR17-92 cluster suppresses stroke-induced neurogenesis and gliogenesis. Western blot analysis showed that miR17-92 cKO significantly (p<0.05) increased and reduced a cytoskeleton-associated protein, Enigma homolog1 (ENH1, 1.6 vs 1.0 fold), and its down-stream transcription factor, inhibitor of differentiation1 (ID1, 1.0 vs 0.6 fold), respectively. ENH1 is a putative target of the miR17-92 cluster.

Conclusion: Our data indicate that the miR17-92 cluster in adult nestin lineage NPCs is required for stroke-induced neurongenesis and gliogenesis, and that the miR17-92 cluster possibly targets ENH1/ID1 signaling.

In these 20 years what changes to your stroke protocols from your doctor have occurred?
ANY AT ALL?
http://journal.frontiersin.org/article/10.3389/fnins.2015.00071/full?

Adult neurogenesis 20 years later: physiological function vs. brain repair

Paolo Peretto^1,2* and Luca Bonfanti^1,3*

• ¹Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
• ²Life Sciences and Systems Biology, University of Turin, Torino, Italy
• ³Department of Veterinary Sciences, University of Turin, Torino, Italy

Two decades of intense investigation in the field of adult neurogenesis (AN) provided us with a fully renewed vision of brain plasticity, involving stem/progenitor cells capable of generating new neurons and glial cells throughout life. We know for sure that new neurons produced within canonical stem cell niches do play a significant role in cognitive tasks (learning/memory) operated by specific neural systems (Lepousez et al., 2013; Aimone et al., 2014). The fact that neural stem/progenitor cells (NSC) produce new elements that can integrate within some regions of the mature brain, replacing lost neurons/glial cells or adding to pre-existent neural circuits, appears extremely fascinating in the perspective of regenerative therapeutic approaches. Since the burst of investigations in AN/NSC field in the nineties, many neurobiologists addressed their studies on brain plasticity in the hope of brain repair, often discussing their results in a translational context. Nevertheless, in spite of striking efforts to clarify mechanisms/factors regulating AN and its physiological function, the question whether it can be exploited for healing neurologic diseases remains unsolved.(This is precisely why we need a strategy) More recent findings revealed additional examples of “non-canonical” neurogenesis and gliogenesis in various regions of the mammalian central nervous system (CNS; reviewed in Bonfanti and Peretto, 2011). These discoveries also open new hopes for brain repair, since the occurrence of spontaneous neuro-gliogenesis within the parenchyma does represent an endogenous source of progenitor cells even outside the restricted environment of canonical neurogenic sites. Nevertheless, parenchymal cell genesis remains substantially obscure as to its functional meaning(s) and outcome(s), and not yet exploitable for brain repair. Such an impasse largely resides on evolutionary discrepancies: most vertebrates use AN for brain repair as a byproduct of evolution, in addition to its physiological functions; mammals have lost such capacity, mainly because of unfavorable environments for repair/regeneration in their mature CNS (Bonfanti, 2011). A scarce perception of these facts might have produced misconceptions among scientists, sometimes leading to attitudes of unconditional optimism.

This Editorial is part of a Frontiers' research topic (and related e-book), gathering 18 articles which were intended to explore the relationships between actual existence of NCSs in mammals (playing homeostatic roles in AN and responding to pathological conditions) and lack of effective reparative outcome in terms of regenerative neurology.

Much more at link.

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

What is your doctor doing with this knowledge to update your stroke protocols and get you closer to 100% recovery? Do not let your doctor deflect the question, your doctor is supposed to help you recover, demand that they do that. 

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

• Ruihe Lin^a,
• Jingli Cai^a,
• Cody Nathan^a,
• Xiaotao Wei^a,
• Stephanie Schleidt^a,
• Robert Rosenwasser^b,
• Lorraine Iacovitti^{a, ,}

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doi:10.1016/j.nbd.2014.11.016

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  Open Access

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Highlights

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Stem cell niches exist along the entire ventricular system in the adult rat brain.

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Stroke induces widespread neurogenesis and gliogenesis in all adult brain niches.

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Niches access systemic injury cues via a permeable BBB, made leakier by stroke.

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All stem cell niches are induced following bFGF infusion into the CSF.

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Abstract

Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14 day) rise in the proliferation (BrdU +) of nestin + Sox2 + GFAP + NSCs capable of differentiating into Olig2 + glial progenitors, GFAP + nestin-astrocyte progenitors and Dcx + neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood–brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.

Coincident Generation of Pyramidal Neurons and Protoplasmic Astrocytes in Neocortical Columns

I still can't quite get a handle on how concerned I should be on knowing what astrocytes do.
http://www.jneurosci.org/content/32/14/4762.short?rss=1

Abstract

Astrocytes, one of the most common cell types in the brain, are essential for processes ranging from neural development through potassium homeostasis to synaptic plasticity. Surprisingly, the developmental origins of astrocytes in the neocortex are still controversial. To investigate the patterns of astrocyte development in the neocortex we examined cortical development in a transgenic mouse in which a random, sparse subset of neural progenitors undergoes CRE/lox recombination, permanently labeling their progeny. We demonstrate that neural progenitors in neocortex generate discrete columnar structures that contain both projection neurons and protoplasmic astrocytes. Ninety-five percent of developmental cortical columns labeled in our system contained both astrocytes and neurons. The astrocyte to neuron ratio of labeled cells in a developmental column was 1:7.4, similar to the overall ratio of 1:8.4 across the entire gray matter of the neocortex, indicating that column-associated astrocytes account for the majority of protoplasmic astrocytes in neocortex. Most of the labeled columns contained multiple clusters of several astrocytes. Dividing cells were found at the base of neuronal columns at the beginning of gliogenesis, and later within the cortical layers, suggesting a mechanism by which astrocytes could be distributed within a column. These data indicate that radial glia are the source of both neurons and astrocytes in the neocortex, and that these two cell types are generated in a spatially restricted manner during cortical development.