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 CNS barriers and become mechanically trapped in peripheral organs. Although the blood-brain barrier and the blood-CSF barrier 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 (i) cells are either engineered to express cell surface proteins mimicking infiltrating immune cells; or (ii) 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 on 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.

Keywords: BBB; brain shuttle; iPSC; stem cells; stroke.

Figure 1

Stem cell administration routes for treating stroke in clinics. Cell grafts can be transplanted into the ischaemic area (IC) or CSF via the ventricles (ICV) or IT injection. Stem cells can also be injected systematically through the IA or IV routes, or cells can be administered IN.

Figure 2

Immune cell transmigration across the BBB. The first step during the transmigration process is known as capture and rolling and is mediated by selectins located in ECs. Second, the interaction between the chemokines and their receptors in immune cells activates the integrins necessary for firm adhesion. Next, diapedesis can occur between ECs (paracellular) or through ECs (transcellular). After interacting with antigen-presenting cells (blue flower-shaped cells), immune cells can secrete metalloproteinases to break the components of the endothelial and parenchymal basement membrane (BM) and eventually enter the brain parenchyma. Upregulated molecules in stroke are indicated with an asterisk in blue. The same letter indicates the interaction partners.

Figure 3

Approaches to enhancing stem cell transmigration to the brain. Stem cells can be modified via genetic or cell membrane engineering to increase the levels of selectin ligands, chemokine receptors, integrins and metalloproteins. These molecules can also be upregulated by preconditioning cells with specific factors or by adjusting culture conditions. These modifications may enable a more efficient migration of cell grafts from the blood circulation to the brain.

Figure 4

Genetic safety systems for eliminating cell grafts in untargeted organs. After cloning a gene encoding for a suicide enzyme, a specific antigen or inducible caspases, cells can be eliminated by adding the corresponding prodrug, MAb or a CID, respectively.