Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke

Stroke is the leading cause of adult disability. Systemic delivery of candidate neural repair therapies is limited by the blood–brain barrier and off-target effects. We tested a bioengineering approach for local depot release of BDNF from the infarct cavity for neural repair in chronic periods after stroke. The brain release levels of a hyaluronic acid hydrogel + BDNF were tested in several stroke models in mouse (strains C57Bl/6, DBA) and non-human primate ( Macaca fascicularis) and tracked with MRI. The behavioral recovery effects of hydrogel + BDNF and the effects on tissue repair outcomes were determined. Hydrogel-delivered BDNF diffuses from the stroke cavity into peri-infarct tissue over 3 weeks in two mouse stroke models, compared with 1 week for direct BDNF injection. Hydrogel delivery of BDNF promotes recovery of motor function. Mapping of motor system connections indicates that hydrogel-BDNF induces axonal sprouting within existing cortical and cortico-striatal systems. Pharmacogenetic studies show that hydrogel-BDNF induces the initial migration of immature neurons into the peri-infarct cortex and their long-term survival. In chronic stroke in the non-human primate, hydrogel-released BDNF can be detected up to 2 cm from the infarct, a distance relevant to human functional recovery in stroke. The hydrogel can be tracked by MRI in mouse and primate.

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Genetic Regulation of Long-Term Nonprogression in E-55+ Murine Leukemia Virus Infection in Mice

Journal of Virology ◽

10.1128/jvi.73.11.9232-9236.1999 ◽

1999 ◽

Vol 73 (11) ◽

pp. 9232-9236

Author(s):

Vily Panoutsakopoulou ◽

Kathryn Hunter ◽

Thomas G. Sieck ◽

Elizabeth P. Blankenhorn ◽

Kenneth J. Blank

Keyword(s):

Bone Marrow ◽

Murine Leukemia Virus ◽

Genetic Locus ◽

Leukemia Virus ◽

Inbred Mouse ◽

Major Histocompatibility Complex Gene ◽

Mouse Strains ◽

Term Survival ◽

Murine Leukemia

ABSTRACT Certain inbred mouse strains display progression to lymphoma development after infection with E-55+ murine leukemia virus (E-55+ MuLV), while others demonstrate long-term nonprogression. This difference in disease progression occurs despite the fact that E-55+ MuLV causes persistent infection in both immunocompetent BALB/c–H-2k (BALB.K) progressor (P) and C57BL/10–H-2k (B10.BR) long-term nonprogressor (LTNP) mice. In contrast to immunocompetent mice, immunosuppressed mice from both P and LTNP strains develop lymphomas about 2 months after infection, indicating that the LTNP phenotype is determined by the immune response of the infected mouse. In this study, we used bone marrow chimeras to demonstrate that the LTNP phenotype is associated with the genotype of donor bone marrow and not the recipient microenvironment. In addition, we have mapped a genetic locus that may be responsible for the LTNP trait. Microsatellite-based linkage analysis demonstrated that a non-major histocompatibility complex gene on chromosome 15 regulates long-term survival and is located in the same region as the Rfv3 gene. Rfv3 is involved in recovery from Friend virus-induced leukemia and has been demonstrated to regulate neutralizing virus antibody titers. In our studies, however, both P and LTNP strains produce similar titers of neutralizing and cytotoxic anti-E-55+ MuLV. Therefore, while it is possible that Rfv3 influences the course of E-55+ MuLV infection, it is more likely that the LTNP phenotype in E-55+ MuLV-infected mice is regulated by a different, closely linked gene.

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Stomach Implant for Long-Term Erythropoietin Expression in Rats

Blood ◽

10.1182/blood.v92.3.888 ◽

1998 ◽

Vol 92 (3) ◽

pp. 888-893 ◽

Cited By ~ 13

Author(s):

Daniel V. Lejnieks ◽

N. Ramesh ◽

Stella Lau ◽

William R.A. Osborne

Keyword(s):

Smooth Muscle ◽

Tissue Oxygenation ◽

Mean Value ◽

Systemic Delivery ◽

Clotting Factors ◽

Term Survival ◽

American Society ◽

Implantation Procedure

Abstract To approach the goal of consistent long-term erythropoietin (Epo) expression in vivo, we developed an implantation procedure in which transduced autologous vascular smooth muscle was introduced into rats in a chamber created from a polytetrafluoroethylene (PTFE) ring placed under the serosa of the stomach. The implant became vascularized and permitted the long-term survival of smooth muscle cells expressing Epo. Hematocrits of treated animals increased rapidly and monitored over 12 months gave a mean value of 56.0 ± 4.0% (P < .001; n = 9), increased from a presurgery mean of 42.3 ± 1.6%. Hemoglobin levels rose from a presurgery mean of 15.2 ± 0.4 g/dL and for 12 months were significantly elevated with a mean value of 19.5 ± 1.3 g/dL (P < .001; n = 9). The hematocrit and hemoglobin levels of control animals receiving human adenosine deaminase (ADA)–expressing cells were not significantly different from baseline (P > .05; n = 5). In response to tissue oxygenation, kidney, and (to a lesser extent) liver are specific organs that synthesize Epo. Treated animals showed downregulation of endogenous Epo mRNA in kidney over a 12-month period. The PTFE implant provides sustained gene delivery, is safe, and is minimally invasive. It allows easy engraftment of transduced cells and may be applied generally to the systemic delivery of therapeutic proteins such as hormones and clotting factors. © 1998 by The American Society of Hematology.

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Stomach Implant for Long-Term Erythropoietin Expression in Rats

Blood ◽

10.1182/blood.v92.3.888.415k30_888_893 ◽

1998 ◽

Vol 92 (3) ◽

pp. 888-893 ◽

Cited By ~ 1

Author(s):

Daniel V. Lejnieks ◽

N. Ramesh ◽

Stella Lau ◽

William R.A. Osborne

Keyword(s):

Smooth Muscle ◽

Tissue Oxygenation ◽

Mean Value ◽

Systemic Delivery ◽

Clotting Factors ◽

Term Survival ◽

American Society ◽

Implantation Procedure

To approach the goal of consistent long-term erythropoietin (Epo) expression in vivo, we developed an implantation procedure in which transduced autologous vascular smooth muscle was introduced into rats in a chamber created from a polytetrafluoroethylene (PTFE) ring placed under the serosa of the stomach. The implant became vascularized and permitted the long-term survival of smooth muscle cells expressing Epo. Hematocrits of treated animals increased rapidly and monitored over 12 months gave a mean value of 56.0 ± 4.0% (P < .001; n = 9), increased from a presurgery mean of 42.3 ± 1.6%. Hemoglobin levels rose from a presurgery mean of 15.2 ± 0.4 g/dL and for 12 months were significantly elevated with a mean value of 19.5 ± 1.3 g/dL (P < .001; n = 9). The hematocrit and hemoglobin levels of control animals receiving human adenosine deaminase (ADA)–expressing cells were not significantly different from baseline (P > .05; n = 5). In response to tissue oxygenation, kidney, and (to a lesser extent) liver are specific organs that synthesize Epo. Treated animals showed downregulation of endogenous Epo mRNA in kidney over a 12-month period. The PTFE implant provides sustained gene delivery, is safe, and is minimally invasive. It allows easy engraftment of transduced cells and may be applied generally to the systemic delivery of therapeutic proteins such as hormones and clotting factors. © 1998 by The American Society of Hematology.

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Deviation of the Fecal Stream in Colonic Bowel Segments Results in Increased Numbers of Isolated Lymphoid Follicles in the Submucosal Compartment in a Novel Murine Model of Diversion Colitis

BioMed Research International ◽

10.1155/2017/5265969 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Annabel Kleinwort ◽

Paula Döring ◽

Christine Hackbarth ◽

Claus-Dieter Heidecke ◽

Tobias Schulze

Keyword(s):

Murine Model ◽

Transverse Colon ◽

Mucosal Inflammation ◽

Mouse Strains ◽

Diversion Colitis ◽

Term Survival ◽

Long Term Survival ◽

Promising Tool ◽

Human Pathology

Introduction.Diversion colitis is a significant health problem due to its high incidence in patients with diverting enterostomy. This mucosal inflammation presents characteristic histopathological features allowing for the differentiation of this entity from other inflammatory bowel diseases. The pathophysiology of this disease remains ill-defined, in part due to the lack of appropriate animal models. The present study was performed in order to develop and characterize a murine model of diversion colitis.Methods.A diverting loop colostomy was performed in C57BL/6 mice either in the ascending colon or in the transverse colon. Animals were assessed for clinical and histopathological parameters during short-term and long-term survival.Results.Animals with a colostomy in the transverse colon showed a good long-term survival and developed a mild colitis in the bypassed bowel closely resembling the human pathology on a histopathological level.Conclusion.This model is a promising tool to further elucidate the pathomechanism leading to impaired mucosal homeostasis in bypassed colonic segments. Moreover, the establishment of the model in the C57BL/6 background allows the combination of this colitis model with various transgenic mouse strains to investigate the effect of locally deregulated mucosal immunity on systemic immune homeostasis and to develop specific therapeutic strategies.

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Gene therapy in hemiparkinsonian rhesus monkeys: long-term survival and behavioral recovery by transplantation of autologous human tyrosine hydroxylase-expressing neural stem cells

Cytotherapy ◽

10.3109/14653240903490371 ◽

2010 ◽

Vol 12 (2) ◽

pp. 226-237 ◽

Cited By ~ 6

Author(s):

Qiang Xu ◽

Xiaodan Jiang ◽

Yiquan Ke ◽

Shizhong Zhang ◽

Ruxiang Xu ◽

...

Keyword(s):

Stem Cells ◽

Gene Therapy ◽

Tyrosine Hydroxylase ◽

Neural Stem Cells ◽

Rhesus Monkeys ◽

Behavioral Recovery ◽

Term Survival ◽

Long Term Survival

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Long-Term Maintenance and Meiotic Entry of Early Germ Cells in Murine Testicular Organoids Functionalized by 3D Printed Scaffolds and Air-Medium Interface Cultivation

Frontiers in Physiology ◽

10.3389/fphys.2021.757565 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guillaume Richer ◽

Robin M. Hobbs ◽

Katherine L. Loveland ◽

Ellen Goossens ◽

Yoni Baert

Keyword(s):

Germ Cells ◽

Mouse Strains ◽

Term Survival ◽

Tissue Degeneration ◽

Testicular Cells ◽

Medium Interface ◽

3D Printed ◽

Cell Functionality ◽

Air Medium

Short-term germ cell survival and central tissue degeneration limit organoid cultures. Here, testicular organoids (TOs) were generated from two different mouse strains in 3D printed one-layer scaffolds (1LS) at the air-medium interface displaying tubule-like structures and Leydig cell functionality supporting long-term survival and differentiation of germ cells to the meiotic phase. Chimeric TOs, consisting of a mixture of primary testicular cells and EGFP+ germline stem (GS) cells, were cultured in two-layer scaffolds (2LSs) for better entrapment. They showed an improved spheroidal morphology consisting of one intact tubule-like structure and surrounding interstitium, representing the functional unit of a testis. However, GS cells did not survive long-term culture. Consequently, further optimization of the culture medium is required to enhance the maintenance and differentiation of germ cells. The opportunities TOs offer to manipulate somatic and germ cells are essential for the study of male infertility and the search for potential therapies.

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Caspases and apoptosis

Essays in Biochemistry ◽

10.1042/bse0380009 ◽

2002 ◽

Vol 38 ◽

pp. 9-19 ◽

Cited By ~ 121

Author(s):

Guy S Salvesen

Keyword(s):

Cysteine Proteases ◽

Signalling Pathways ◽

Term Survival ◽

Mature Adult ◽

Intracellular Signalling Pathways ◽

Adult Cell ◽

Caspase Family ◽

Cell Fragments ◽

Pro Inflammatory Cytokines

The ability of metazoan cells to undergo programmed cell death is vital to both the precise development and long-term survival of the mature adult. Cell deaths that result from engagement of this programme end in apoptosis, the ordered dismantling of the cell that results in its 'silent' demise, in which packaged cell fragments are removed by phagocytosis. This co-ordinated demise is mediated by members of a family of cysteine proteases known as caspases, whose activation follows characteristic apoptotic stimuli, and whose substrates include many proteins, the limited cleavage of which causes the characteristic morphology of apoptosis. In vertebrates, a subset of caspases has evolved to participate in the activation of pro-inflammatory cytokines, and thus members of the caspase family participate in one of two very distinct intracellular signalling pathways.

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