Elsevier

Journal of Controlled Release

Volume 162, Issue 2, 10 September 2012, Pages 464-473
Journal of Controlled Release

Review
Mesenchymal stem cells as therapeutic agents and potential targeted gene delivery vehicle for brain diseases

https://doi.org/10.1016/j.jconrel.2012.07.034Get rights and content

Abstract

Transplantation of mesenchymal stem cells (MSCs) into the injured brain may provide therapeutic benefits. Several models of brain diseases have been examined, including that of ischemic stroke, neurodegenerative diseases and brain tumors. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, using genetically engineered MSCs as the delivery vehicles. Genetically engineered and surface modified methods are supposed to enhance the migration of MSCs toward brain lesions. The current data in support of applying MSC-based cellular therapies to the treatment of brain disorders are discussed.

Graphical abstract

Highlights

► MSCs can be efficiently genetically engineered and surface modified. ► Geneticaly engineered and surface modified methods are supposed to enhance the targeting capability of MSCs. ► MSCs are promising therapeutic agents and potential targeted gene delivery vehicle for some brain diseases.

Introduction

Human brain diseases, including ischemic stroke, glioma and neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remain serious problems that currently have no effective treatments. Most of brain diseases lead to a localized loss of neurons. The transplantation of stem cells may repair injured nervous tissue through replacement of damaged cells, hence providing an effective treatment for brain diseases. Stem cells are well known for the self-renewing capacity and multipotential nature like high differentiation and “homing” capability, which provides the solid foundation of treatment for various diseases. Different populations of adult stem cells that can contribute to the regeneration of muscle, liver, heart and vasculature have been described, although the mechanisms by which this is accomplished are still not completely understood [1]. Several types of stem cells have been transplanted into the injured brain, including mesenchymal stem cells (MSCs) [2], [3], [4], [5]. MSCs have been found to produce improvements in disease models, although a limited number of the cells could be demonstrated to be stably engrafted. The injected mesenchymal stem cells home to the injured area, in particular to hypoxic, apoptotic or inflamed areas, and release trophic factors that hasten endogenous repair [1]. The basic theory of stem cell therapy is that stem cells would replace injured cells, which seems to be a part of theories in the treatment for brain diseases. However, other mechanisms are proposed, including the possibility that stem cells may release or stimulate release of trophic factors which would be neuroprotective, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate recruitment, retention, proliferation and differentiation of tissue-residing stem cells [1].

Some innate functions of MSCs determine the utility for cell therapy. MSCs were observed mainly in the lungs, liver, kidney and skin after systemic transplantation in noninjury models [6]. While in some diseases models, systemically infused MSCs home to injured, inflamed tissues [7], [8]. Collective evidences have shown that MSCs accumulated in the lungs right after systemic infusion, then most MSCs moved gradually to injured sites [6], [9], [10], [11] or to other organs like liver, spleen, kidney, and bone marrow [12]. In these organs, MSCs persisted as long as several months [9], [13], [14], although the percentage of engrafted MSCs were very low while some died as inappropriate environment for stem cells surviving. However, a limited number of cells that are stably engrafted indeed produce improvements in some diseases [15], [16], [17]. Their efficacy may rely on the collaboration of secretion of cytokines and direct differentiation. It has been demonstrated that MSCs can promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons [18]. Besides the neurotrophic factors, MSCs can produce the extracellular matrix molecules that can support neural cell attachment, growth and axonal extension [19]. Several studies have proved that MSCs can be induced to express neural markers in vitro [20], [21], while after stem cells migrating in the brain, some new neurons in the adult human hippocampus have been found [18], [22], [23]. There is no precise definition of mechanisms of stem cell‐based therapy for brain diseases yet; however, as beneficial effects have been demonstrated, details inside cell therapy need further investigation.

In addition to the advanced research into the precise mechanisms, strategies should also be established to enhance the homing capability of MSCs towards brain lesions for better therapeutic effects as well as reducing side effect. Otherwise, although some available results from small clinical studies support the overall safety of this cell therapy, and MSCs are known to be non-immunogenic, the risk of injection is not eliminated, especially for direct infusion of MSCs into the brain, the safety issues should be extremely carefully, while more details about the safety issues should be evaluated before clinical application, such as tumor formation, ectopic activity and unwanted fibrosis included in long-term effects. It is also worth paying attention to the appropriate control of stem cell‐based therapy, as there are no enough strong evidences to support its biosafety. The aim of this review is to elucidate the role of MSCs for the treatment of brain diseases with addressing the potential homing ability of MSCs and possible methods to enhance their targeting capacity. Further studies must be conducted in order to have a better understanding of the distribution of infused MSCs in the brain, and the mechanisms that attract them towards the damaged tissues. This knowledge will allow the most effective use of MSC-based cellular therapies.

Section snippets

Stem cell‐based cell therapy in brain diseases: An overview

Cell replacement and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases including stroke, neurodegenerative diseases such as Parkinson disease, Huntington disease, and Alzheimer disease, and also brain tumors. Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat brain diseases. Recent

MSCs for the treatment of brain diseases

Mesenchymal stem cells (MSCs) and gene-engineered MSCs have shown therapeutic benefits in treating brain diseases such as stroke, neurodegenerative diseases and brainstem glioma. Proposed approaches include delivery via intracerebral or intravenous injection, or even infusion via an intranasal route [37]. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and

MSCs for potential targeted therapy of brain diseases

The capacity of direct migration to the lesions is vital to stem cell-based therapies. Studies have demonstrated the ability of MSCs migration towards and incorporation with tumors, since the cytokines, chemokines and other inflammatory factors produced by tumors could recruit MSCs [81], [82]. Similar with tumors, recent studies have shown that MSCs hold the natural potential to home to injured sites of the brain, such as ischemic tissues and tumors [40], [74], thus making them excellent

Clinical outlook

The feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke were assessed by Bang et al. [116]. Thirty patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits were enrolled in the MSC clinical trial with no adverse events. MSCs were isolated from the patients’ own bone marrow and intravenously injected after ex vivo culture expansion. Changes in neurological deficits and

Conclusion and future perspective

We review current situation of MSC-based therapies for the treatment of brain diseases, and highlight the potential role of MSCs as targeted therapeutic agent or vehicle. As MSCs have the ability to cross the BBB and preferentially migrate to the injured sites, they hold potential to target towards brain lesions with some proper modification. Gene modification and surface coating are under investigation, and more effective methods should be introduced to enhance the migration capability of MSCs.

Acknowledgement

This work was financially supported by National Natural Science Foundation of China (30873173, 81001410), the Fundamental Research Funds for the Central Universities, China, and the China‐Japan Scientific Cooperation Program (81011140077) supported by both NSFC, China and JSPS, Japan.

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