Creating a graft-friendly environment for stem cells in diseased brains

Abstract

Most of the adult CNS lacks regenerative activity in terms of both neuron birth and neurite outgrowth. While this regeneration-unfriendly environment of the adult CNS may preserve the existing neuronal circuitry that takes years to develop in higher organisms, it also poses a major obstacle for CNS repair later in life. In this issue of the JCI, Song et al. report on their development of a strategy that uses region-specific and molecularly engineered astrocytes to turn an unfavorable brain environment into a favorable one for engrafted neural stem/progenitor cells (NSC/NPCs). In a rat model of Parkinson's disease (PD), cografting NPCs with midbrain-derived astrocytes engineered to overexpress the transcription factors Nurr1 and Foxa2 promotes maturation and survival of the graft, resulting in therapeutic improvement. The results of this study raise the prospect of using modified astrocytes to improve the survival, maturation, and integration of engrafted NSC/NPCs as a restorative treatment for PD.

Figure 1. Host environment influences outcome of NSC/NPC transplantation in a rat model of PD.

NSC/NPCs transplanted along with neurotrophic astrocytes create a friendly environment that allows their differentiation and maturation into mDA neurons. Neurotrophic astrocytes release several classes of molecules that promote mDA neuron differentiation and support long-term survival of these neurons. These include antiinflammatory cytokines (anti-iCKs), such as INF-α, INF-β, IL-1R, CCL17, and CCL22; anti-ROS molecules, including SOD3 and GPX; neurotrophic factors, such as GDNF, SHH, BDNF, NTF3, and Wnts; and neurotrophic ECM proteins, including FN1, COL6A2, ITGβ4, ITGαM, THBS1, and GPC. The presence of stress introduced by the transplantation procedure can cause neurotrophic astrocytes to become immunogenic, creating a hostile environment for transplanted NSC/NPCs. Immunogenic astrocytes hinder the maturation and survival of mDA progenitors through the production of proinflammatory cytokines (iCKs), such as IL-1β, TNF-α, iNOS, IL-6, and CXCL11, and myelin-associated proteins (MAP), including MBP, MOG, and MAG. Induced expression of Nurr1 and Foxa2 tips astrocytes toward a neutrophic phenotype, thereby promoting the maturation and survival of donor cell–derived mDA neurons. TH, tyrosine hydroxylase; nECM, neurotrophic ECM.