Co-transplantation strategies and combination therapies for stroke

Abstract

Worldwide cerebrovascular disease (CVD) is increasing in parallel with modernization, changes in lifestyle, and the growing elderly population. The incidence of stroke increases significantly with age both in men and women with incidence rates accelerating above 70 years. Since stroke afflicts mostly the elderly comorbid patients, it is highly desirable to test the efficacy of cell therapies in an appropriate animal stroke model. All monotherapeutic attempts to prevent or ameliorate brain damage following stroke have failed so far. In view of previous findings indicating that stroke impacts a wide range of mechanisms, ranging from central nervous system (CNS) physiology over CNS regeneration and plasticity to the adaptive immune system in an age-dependent manner, the failure of monotherapies is perhaps not unlikely. Bone marrow-derived mesenchymal stem cells (BM MSCs) and hematopoietic stem/progenitor cells (HSPC) are the most frequently cells used in preclinical and clinical neurorestorative studies in stroke therapy. Therefore co-transplantation of BM MSCs with other cells may be a better strategy to improve microenvironment, make the grafting more efficient, and improve functional recovery after stroke. Current knowledge includes: (1) the potential for neurogenesis is also preserved in aged, stroke-injured brains; (2) the environment of the aged brain is not hostile to transplantation of BM MSC; and (3) the extent of recovery is successful in some but not all behavioral tests. However, there remain significant developmental and translational issues to be resolved in future studies such as: (1) Understanding the differentiation into specific phenotypes. Upon transplantation, the differentiated cells often de-differentiate (Kalladka and Muir Stem Cells Cloning 7:31-44, 2014). (2) Tumorigenesis remains a significant concern (Riess et al. J Neurotrauma 24(1):216-225, 2007). (3) Anti-neuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. (iv) Efficacy of cell therapy can be enhanced by physical rehabilitation (Dunnett Clin Neurol 110:43-59, 2013). We recommend that in a real clinical practice involving older poststroke patients, successful regenerative therapies would have to be carried out for a much longer time. The BM MSC therapy in aged rodents warrants further investigation including repeated administrations of therapeutic cells at several time points after stroke and using various combinations with G-CSF or other relevant growth factors/cytokines. Finally, a better understanding of potential risks of stem cell therapies in strokes shall makes the translation of cell therapies safer. Likewise, awareness of their biology may help improve their efficacy to achieve therapeutic success.