Stroke is the fourth leading cause of mortality in the USA; every year almost 750,000 people have a new stroke Citation[1]. Since stroke is the leading cause of adult disability Citation[1], there is an urgent public health need to develop new treatments. The application of cell-based therapies is an emerging technology for cerebrovascular disorders Citation[2,3]. For acute ischemic stroke, tissue plasminogen activator is the only approved therapy that promotes recanalization of occluded cerebral arteries; however, only a minority of patients are eligible to receive it Citation[4] because the drug must be administered within 3–4.5 h after symptom onset. Once damage from stroke has maximized, little can be done to recover premorbid function. There are no approved effective treatments to reverse or repair brain damage associated with stroke, and the brain possesses only limited repair mechanisms. New therapeutic approaches using cells, rather than drugs, show much promise to promote repair of the injured brain. Among the various types of ‘cell therapies’, there are different kinds of cells that fall into the categories of embryonic, fetal and adult cell types, all of which are under development as potential new treatments for stroke. A growing body of extensive animal data suggest that cell therapies derived from a range of tissues (whether they are embryonic, fetal or adult) improve neurological outcome in rodent models of stroke Citation[5–8].
Stem cell therapy has been shown in early proof-of-concept studies to treat selected patients with Parkinson’s disease through transplantation of fetal tissue containing stem cells Citation[9]. However, transplantation of stem cells in stroke is far more complicated than just replacing infarcted tissue. Most of the evidence supporting the use of cell therapies from animal models is based on the concept that the cells release factors that stimulate the brain’s endogenous repair mechanisms. Some types of cell therapies stimulate the brain parenchyma to secrete neurotropic factors such as basic FGF and brain-derived neurotropic factor, which activate pathways leading to enhanced survival, proliferation, differentiation and migration of neural progenitor cells Citation[10]. An increase in progenitor oligodendrocytes has been observed at the site of the ischemic lesion after the administration of cell therapies, leading to an enhancement in myelination. Hence, these mechanisms may play a role in the regeneration and repair processes of cell therapy in ischemic stroke Citation[10]. Both angiogenesis and neurogenesis occur in the adult brain after injury and are regulated by similar mechanisms Citation[11]. Many types of cell therapies also release bioactive factors that stimulate neurogenesis and angiogenesis in areas proximal to the infarct.
Another major mechanism underlying how some types of cell therapies exert their effects is by modulation of the immune/inflammatory response after stroke. Different types of cell therapies have been shown to express anti-inflammatory cytokines, which may reduce secondary damage due to poststroke inflammation Citation[12]. Some types of cell therapies may reduce peripheral immune responses emanating from the spleen Citation[13] and lungs Citation[14]. These emerging data support the concept that the cell therapies can convert peripheral organs into bioreactors that are anti-inflammatory and proregenerative after a stroke.
Given more than a decade of research in rodent stroke models, a small number of clinical trials testing cell-based therapies in patients with ischemic stroke have been completed and several more are underway or being planned. The initial clinical trials in this field involved fetal tissue sources. However, given that human fetal brain tissue and other embryonically derived tissues are a limited and ethically challenging resource, more than 10 years ago the field moved toward alternative tissue sources derived from adults and birth-related tissues such as umbilical cord and placenta. Cells from these sources are more readily amenable to widespread clinical application and have been studied to a greater extent than fetal or embryonic tissues in animal stroke models. The most widely studied cells brought forward to clinical studies are bone marrow mesenchymal stromal cells (MSCs) and bone marrow mononuclear cells (MNCs).
Our group published a pilot trial on the safety and feasibility of intravenously administered autologous bone marrow-derived MNCs in ten patients with acute ischemic stroke. There were no severe adverse events associated with the bone marrow harvest or infusion Citation[6]. At least two further pilot studies have been conducted in stroke patients testing the intra-arterial infusion of autologous MNCs within 1 week after stroke Citation[15,16]. Several small studies have also been conducted testing the safety of autologous bone marrow-derived MSCs in the chronic setting of stroke in Korea Citation[17,18], Japan Citation[19] and India Citation[20]. Unlike MNCs, which can be separated from marrow within hours, MSCs require weeks of passage in culture, but they may carry a wider therapeutic window than MNCs. Overall, there were no signals of safety concerns in any of these trials. Since the initiation of these investigator-initiated, autologous cell studies, industry-sponsored trials have begun testing new types of manufactured stem cells. For example, Aldagen is conducting a study on the safety of aldehyde dehydrogenase bright cells administered by intracarotid injection in patients with subacute stroke, while Athersys, Inc. (OH, USA) is conducting a trial testing their allogeneic cell product (Multistem®), an adherent purified bone marrow stem cell, in patients with acute ischemic stroke.
In our opinion, the field of cell therapy is a very exciting area to develop potential new therapies for stroke. However, the field is still too much in an embryonic stage to draw conclusions on its viability as a treatment for stroke or any other neurological disorder. Much more research is needed. There are many unanswered questions surrounding the best cell types, optimal delivery routes, therapeutic time windows and appropriate patients. Adult-derived cells are the most attractive cells because they permit autologous applications. Equally attractive are purified allogeneic cells that can be derived from healthy volunteers or birth-associated tissues and may not require immunosuppressive agents. Systemic administration, mainly by intravenous delivery, is the most practical, but pulmonary trapping is an important consideration for some cell types, motivating some investigators to focus on intra-arterial delivery routes. The use of fetal and embryonic-derived neural stem cells, however, have made significant advancements in stroke research, and one clinical trial is in Phase I, testing an intracranial delivery of immortalized neural stem cells. Direct or stereotactic injections do need to be well justified given the invasiveness of the procedure. Therapeutic windows still require more data in animals and depend on the intended goals and targets – inflammation, repair, tissue replacement and so on. MNCs, for example, may have shorter therapeutic windows and thus may be better suited for acute/subacute windows, whereas MSCs could possibly be used in subacute to chronic windows. As trials are now advancing to randomized controlled two-arm studies, we will learn in the near future about possible signals of efficacy in this field, but we are still several years away from knowing if any type of cell therapy will prove to be an effective treatment for stroke.
Financial & competing interests disclosure
The authors were funded by the Howard Hughes Medical Institute and the NIH to conduct research in cell therapies in stroke: grant numbers R01NS071127, R21HD060978, R21NS06316 and T31NS007412. SI Savitz served as the senior investigator for the Aldagen clinical trial. SI Savitz undertakes sponsored research with Aldagen, Celgene, Athersys and J&J, and serves as a consulant for Neuralstem and KM Phamaceutical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics – 2012 update.Circulation doi:10.1161/CIR.0b013e31823ac046 (2012) (Epub ahead of print).
- Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ. Res. 109(8), 923–940 (2011).
- Chen J, Zhang ZG, Li Y et al. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ. Res. 92(6), 692–699 (2003).
- Kleindorfer D, Lindsell CJ, Brass L, Koroshetz W, Broderick JP. National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke 39(3), 924–928 (2008).
- Mattle HP, Savitz SI. Advances in emerging therapies 2010. Stroke 42(2), 298–300 (2011).
- Savitz SI, Misra V, Kasam M et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann. Neurol. 70(1), 59–69 (2011).
- Honma T, Honmou O, Iihoshi S et al. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp. Neurol. 199(1), 56–66 (2006).
- Onda T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J. Cereb. Blood Flow Metab. 28(2), 329–340 (2008).
- Freed CR, Greene PE, Breeze RE et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344(10), 710–719 (2001).
- Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 8(5), 491–500 (2009).
- Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25(9), 1794–1798 (1994).
- Guzman R, Choi R, Gera A, De Los Angeles A, Andres RH, Steinberg GK. Intravascular cell replacement therapy for stroke. Neurosurg. Focus 24(3–4), e15 (2008).
- Ajmo CT Jr, Collier LA, Leonardo CC et al. Blockade of adrenoreceptors inhibits the splenic response to stroke. Exp. Neurol. 218(1), 47–55 (2009).
- Németh K, Leelahavanichkul A, Yuen PS et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15(1), 42–49 (2009).
- Moniche F, Gonzalez A, Gonzalez-Marcos JR et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 43(8), 2242–2244 (2012).
- Friedrich MA, Martins MP, Araújo MD et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 21(Suppl. 1), S13–S21 (2012).
- Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann. Neurol. 57(6), 874–882 (2005).
- Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY; STARTING collaborators. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28(6),1099–1106 (2010).
- Honmou O, Houkin K, Matsunaga T et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134(Pt 6), 1790–1807 (2011).
- Bhasin A, Srivastava MV, Kumaran SS et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc. Dis. Extra 1(1), 93–104 (2011).