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Transplantation of glial enriched progenitors provides therapeutic effects on axonal damage, cognitive and motor function following white matter stroke. [ABSTRACT FROM AUTHOR]

Stroke is a major cause of serious disability due to the brain's limited capacity to regenerate damaged tissue and neuronal circuits. After ischemic injury, a multiphasic degenerative and inflammatory response is coupled with severely restricted vascular and neuronal repair, resulting in permanent functional deficits. Although clinical evidence indicates that revascularization of the ischemic brain regions is crucial for functional recovery, no therapeutics that promote angiogenesis after cerebral stroke are currently available. Besides vascular growth factors, guidance molecules have been identified to regulate aspects of angiogenesis in the central nervous system (CNS) and may provide targets for therapeutic angiogenesis. In this study, we demonstrate that genetic deletion of the neurite outgrowth inhibitor Nogo-A or one of its corresponding receptors, S1PR2, improves vascular sprouting and repair and reduces neurological deficits after cerebral ischemia in mice. These findings were reproduced in a therapeutic approach using intrathecal anti-Nogo-A antibodies; such a therapy is currently in clinical testing for spinal cord injury. These results provide a basis for a therapeutic blockage of inhibitory guidance molecules to improve vascular and neural repair after ischemic CNS injuries. [ABSTRACT FROM AUTHOR]

The brain is not immune privileged, leading to new challenges for cell therapies. While cell therapies for stroke have been shown to enhance recovery in animal studies, their move into clinical reality needs to be reassessed from an immunological perspective. A major hurdle in allogeneic cell transplantation is the low immunocompatibility due to human leukocyte antigen (HLA) mismatches. Finding an HLA match for unrelated individuals is 1 in 100 000, and hundreds of homozygous cell lines are needed for most of the population. Modifying HLAs and related genes in cell grafts has improved immune compatibility in animal studies, setting the stage for human trials. HLA engineering offers a means to bypass the host immune response and reduce cells required for the HLA spectrum. However, these cell sources introduce safety challenges, addressed with genetic safety mechanisms. Stem cell therapy is an emerging treatment paradigm for stroke patients with remaining neurological deficits. While allogeneic cell transplants overcome the manufacturing constraints of autologous grafts, they can be rejected by the recipient's immune system, which identifies foreign cells through the human leukocyte antigen (HLA) system. The heterogeneity of HLA molecules in the human population would require a very high number of cell lines, which may still be inadequate for patients with rare genetic HLAs. Here, we outline key progress in genetic HLA engineering in pluripotent stem and derived cells to evade the host's immune system, reducing the number of allogeneic cell lines required, and examine safety measures explored in both preclinical studies and upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Stroke patients have only limited therapeutic options and often remain with considerable disabilities. To promote neurological recovery, angiogenesis in the ischemic peri-infarct region has been recognized as an encouraging therapeutic target. Despite advances in mechanistic understanding of vascular growth and repair, effective and safe angiogenic treatments are currently missing. Besides the most intensively studied angiogenic growth factors, recent research has indicated that the process of vascular sprouting and migration also requires the participation of guidance molecules, many of which were initially identified as regulators of axonal growth. Here, we review the inhibitory and growth-promoting effects of guidance molecules on the vascular system and discuss their potential as novel angiogenic targets for neurovascular diseases. During development, guidance molecules regulate both cell migration and blood vessel growth in many organs, including the central nervous system (CNS). These guidance molecules can act as pro- or antiangiogenic cues. Growing evidence indicates that in the adult brain, guidance molecules play important roles in neurovascular stability. Following ischemic injury, many guidance molecules are upregulated in ischemic areas in the CNS and other organs. Interference with guidance molecules following ischemic injury can affect vascular repair and regeneration and thus influence functional outcomes in preclinical models including cerebral stroke. So far, experimental proangiogenic approaches in the CNS have mostly focused on VEGF supplementation, with limited success partly due to detrimental effects of the treatment, including increased blood–brain barrier (BBB) leakage. Some guidance molecules have proangiogenic properties without apparent negative effects on the BBB. Guidance molecules and their receptors, given their potential dual positive effects on both nerve fiber and vascular regeneration, may represent advantageous targets for the development of new therapies to 'refuel' and repair the damaged CNS. [ABSTRACT FROM AUTHOR]