Editing a gateway for cell therapy across the blood–brain barrier

Abstract

Stem cell therapy has been shown to improve stroke outcomes in animal models and is currently advancing towards clinical practice. However, uncertainty remains regarding the optimal route for cell delivery to the injured brain. Local intracerebral injections are effective in precisely delivering cells into the stroke cavity but carry the risk of damaging adjacent healthy tissue. Systemic endovascular injections, meanwhile, are minimally invasive, but most injected cells do not cross central nervous system (CNS) barriers and become mechanically trapped in peripheral organs. Although the blood–brain barrier (BBB) and the blood–cerebro spinal fluid barrier (BCSFB) tightly limit the entrance of cells and molecules into the brain parenchyma, immune cells can cross these barriers especially under pathological conditions, such as stroke. Deciphering the cell surface signature and the molecular mechanisms underlying this pathophysiological process holds promise for improving the targeted delivery of systemic injected cells to the injured brain. In this review, we describe experimental approaches that have already been developed in which (a) cells are either engineered to express cell surface proteins mimicking infiltrating immune cells or (b) cell grafts are preconditioned with hypoxia or incubated with pharmacological agents or cytokines. Modified cell grafts can be complemented with strategies to temporarily increase the permeability of the blood–brain barrier. Although these approaches could significantly enhance homing of stem cells into the injured brain, cell entrapment in off-target organs remains a non-negligible risk. Recent developments in safety-switch systems, which enable the precise elimination of transplanted cells upon the administration of a drug, represent a promising strategy for selectively removing stem cells stuck in untargeted organs. In sum, the techniques described in this review hold great potential to substantially improve efficacy and safety of future cell therapies in stroke and may be relevant to other brain diseases.

The role of the blood–brain barrier during neurological disease and infection

“…To overcome this hurdle, several innovative approaches are currently being developed. Some of the novel techniques include, using receptor-mediated transcytosis to deliver nanoparticles [ 187 ], cell-penetrating peptide conjugated adeno-associated viruses (AAVs) to deliver novel gene therapies [ 188 ], organic cation transporters 1 and 2 (Oct1/Oct2) to deliver novel stroke therapeutics [ 189 ], intranasal delivery methods [ 190 ], cell therapies [ 191 ] and focused ultrasound (FUS) in conjunction with gas-filled microbubble contrast agents [ 192 ]. Finally, to make progress, the development of suitably robust and reliable in vitro BBB models for high throughput drug screening as well as models that can mimic the complex pathophysiology of BBB dysfunction to elucidate the underlying mechanisms are essential.…”

Experimental models for cancer brain metastasis

“…The BBB is a selective safeguard barrier for the brain, permitting the entry of essential nutrients while restricting hazardous substances. 9 , 10 It consists of endothelial cells lining the blood vessels, along with astrocytes/pericytes enveloping the vessels to maintain BBB integrity and permeability. 11 , 12 The Transwell devices are widely used to model the BBB in vitro .…”

Revolutionizing Stroke Recovery: Unveiling the Promise of Stem Cell Therapy

“…Significant research is dedicated to elucidating the mechanisms of immune cell trafficking across the blood -brain barrier (BBB) and how these pathways can be leveraged to improve the targeted delivery of stem cells to the brain. 7 Experimental strategies that have been developed to enhance stem cell migration, including genetic engineering to express specific cell surface proteins mimicking immune cells, cell membrane engineering, stem cell selection and preconditioning, and methods to temporarily increase BBB permeability. 7 …”

“… 7 Experimental strategies that have been developed to enhance stem cell migration, including genetic engineering to express specific cell surface proteins mimicking immune cells, cell membrane engineering, stem cell selection and preconditioning, and methods to temporarily increase BBB permeability. 7 …”