Skip to main content

Ischemic stroke and repair: current trends in research and tissue engineering treatments


Stroke, the third leading cause of mortality, is usually associated with severe disabilities, high recurrence rate and other poor outcomes. Currently, there are no long-term effective treatments for stroke. Cell and cytokine therapies have been explored previously. However, the therapeutic outcomes are often limited by poor survival of transplanted cells, uncontrolled cell differentiation, ineffective engraftment with host tissues and non-sustained delivery of growth factors. A tissue-engineering approach provides an alternative for treating ischemic stroke. The key design considerations for the tissue engineering approach include: choice of scaffold materials, choice of cells and cytokines and delivery methods. Here, we review current cell and biomaterial based therapies available for ischemic stroke, with a special focus on tissue-engineering strategies for regeneration of stroke-affected neuronal tissue.



Stroke is the third leading cause of disease mortality worldwide. In the United States, about 150,000 individuals die of stroke every year [1]. Ischemic stroke is caused by interruption of the cerebral blood supply, accounting for about 80% of all stroke cases [2]. Depending on the regions where ischemic stroke occurs, it can impair patients’ capabilities of sensory processing, communication, cognition and motor function [3]. Motor impairment associated with stroke often leads to short-term or permanent disabilities, substantially affecting patients’ life quality [4]. In addition, stroke increases the risk of Parkinson’s disease and Alzheimer’s disease [5].

Currently, there are no long-term effective clinical treatments available for stroke as few of them leads to complete functional recovery [6, 7]. The intravenous administration of tissue-type plasminogen activator (tPA) is a proven intervention for acute ischemic stroke patients [8]. However, this treatment is only applicable to a small percentage of stroke patients in the acute phase as its therapeutic time window is rather narrow (up to 4.5 hours after the onset of symptoms) [9]. Meanwhile, this treatment was reported to increase the risk of intracranial hemorrhage [10]. Physical therapy is often used to restore motor function after stroke [4, 11, 12]. However, 15–30% of stroke patients are still permanently disabled even with intensive task-­specific training [4, 13]. Early motor training and physical therapy might impede functional recovery and enlarge lesion size as suggested by animal experiments [14, 15]. Thus, few of these treatments can lead to complete functional recovery. Cell and cytokine therapies [1623] have been explored previously. The regeneration outcome of this therapy is often limited due to poor cell survival, uncontrolled in vivo differentiation of delivered cells, ineffective integration of delivered cells with the host tissue and non-sustained delivery of growth factors.

These limitations may be overcome by employing a tissue engineering strategy. Tissue-engineered scaffolds can provide a highly biocompatible three-dimensional environment that supports the long-term growth of therapeutic cells seeded on the scaffolds, thus improving the in vivo survival of these cells. Meanwhile, the scaffold can act as a drug delivering vehicle releasing neuro-protective factors in a controlled manner, which promotes the regeneration and functional recovery of damaged neuronal tissue [16]. In this review, we summarize current therapies for ischemic stroke, with a special emphasis on the important aspects of the tissue-engineering strategy for stroke treatment.

Cell therapy

Various types of cells have been investigated for their potential to regenerate damaged neural tissue caused by ischemic stroke (Table 1).

Table 1 Cell therapy used in the treatment of stroke

Neural stem cells

Neural stem cells (NSCs) can be obtained from along the entire neuraxis of adult central nervous system (CNS) [2427]. NSCs have been experimentally utilized to treat CNS disorders, including stroke [28, 44]. The intracranial injection of NSCs isolated from rat subventricular zone (SVZ) into a rat stroke model, middle cerebral artery occlusion (MCAO), led to sensory and motor recovery [28].

Human neural stem cells (hNSCs) have also been applied into the treatment of neuronal disorders. These cells are isolated from the embryonic or fetal CNS [44]. The human neurospheres derived from these hNSCs can survive robustly in naive and ischemic brains [20]. When hNSCs were injected directly into the stroke-damaged striatum of adult rats, these cells differentiated and expressed mature neuronal markers, such as calbindin, HuD and parvalbumin [45], indicating that transplanted NSCs remain competent to differentiate into functional neurons. This result is consistent with another study, which showed that after implanted into the damaged central nervous system of ischemic rats, a fraction of the grafted neural stem cells were able to differentiate into neurons in vivo and promote function recovery [29]. Although NSCs showed a great potential in treating cerebral ischemic lesion, many problems remain, for instance, the low in vivo survival rate of these cells, immune rejection and ethical issues.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs), presented in the bone marrow, are multipotent adult stem cells with the capabilities of differentiating into various cell types, including neurons [31, 32]. MSCs can differentiate into neurons in vitro in an experimentally controlled manner. When cultured with differentiation factors (e.g. β-mercaptoethanol and dimethylsulfoxide) [32], growth factors (e.g. fibroblast growth factor-2 (FGF2) and epidermal growth factor (EGF) [46], brain-derived neurotrophic factor (BDNF) [47] or retinoic acid (RA) [48]), these MSCs express neuronal markers (neuron-specific endonuclease, NeuN neurofilament-M, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase, and β-III-tubulin) [46]. MSCs were reportedly to be able to survive and migrate into lesion sites after transplanted into the experimental models of stroke [49]. Moreover, the intravenous injection of MSCs was found to promote functional recovery in the animal stroke MCAO model [33]. This function recovery resulted from MSCs treatment may be associated with reduced scar thickness and the increased number of oligodendrocyte precursor cells and proliferating cells along the SVZ [34]. Notably, the therapeutic effects of MSCs on stroke have been recently evaluated in several clinical trials. In a small trial, the intravenous infusion of autologous MSCs significantly improved functional recovery without obvious adverse effects during one-year follow-up [50]. Similar recovery effects were also observed in a long-term clinical trial with 52 stroke patients [51]. Compared with NSCs, MSCs appear to be more conveniently obtained. Autologous MSCs can reduce immunologic rejection and bypass ethical issues. Nonetheless, like NSCs, the application of MSCs for stroke treatment faces the similar challenges, such as poor in vivo cell viability.

Stimulation of endogenous neurogenesis

While stroke patients may benefit from neuronal regeneration mediated by exogenously delivered stem cells, stimulating endogenous neurogenesis by activating brain resident cells for neuronal repair can be another potential approach for treating stroke. In response to stroke or other brain injury, the degree of endogenous neurogenesis, neurite outgrowth and functional recovery are often constrained [5256]. There are two main regions of the adult brain that contain proliferating progenitor cells: the SVZ and the subgranular zone (SGZ) [57]. While under normal conditions the quiescent ependymal cells do not contribute to neurogenesis, these cells can be activated to give rise to neuroblasts and astrocytes in response to stroke [58]. One way to stimulate endogenous neurogenesis in the SVZ is reportedly to use BDNF fused with a collagen-binding domain (CBD-BDNF) as a stimulant [59]. The injection of CBD-BDNF into the lateral ventricle of MCAO rats was shown to promote local neural regeneration, angiogenesis and improve functional recovery [59].

Induced pluripotent stem cells

Dating back to the recent breakthroughs in the stem cell field, induced pluripotent stem (iPS) cells, one of the most exciting improvements, have been generated from a host of human somatic cells since their original characterization in 2007 [60]. The obvious similarities they share with embryonic stem cells, including the ability to differentiate into all cell types composing the tissues of the body, turn out to be much remarkable.

It seems more attractive to clinical applications as iPS cells generated from a patient can be applied for treatment of various diseases in an autologous manner. Transplantation of iPS cells has been experimentally tested for treating stroke. A mixture containing iPS cells and fibrin glue was delivered into the subdural space following MCAO. This treatment decreased total infarct volume and significantly improved the motor function (rotarod and grasping tasks) [61]. A notable reduction in pro-inflammatory cytokines and a simultaneous increase in the anti-inflammatory cytokines were also observed [61]. However, another study showed the formation of tridermal teratoma in the brain after being transplanted with undifferentiated iPS cells into the ipsilateral striatum and the cortex of rats following the transient MCAO [62]. Although the control over in vivo differentiation of iPS cells needs further study, it is undeniable that iPS cells will continue to be a focus of the cell therapy for a variety of neurodegenerative diseases, including stroke [63].


A plethora of biomaterials have been investigated for their potential to treat stroke (Table 2) [64]. An ideal biomaterial for stroke treatment is expected to meet several requirements: first, it must have specific physical and biochemical properties allowing cell to attach to it, proliferate and differentiate on it, migrate off to integrate with host neuronal tissue [16, 17]. Second, it should degrade in vivo to permit tissue healing and growth. Moreover, its degradation products should be highly biocompatible, non-cytotoxic, non-inflammatory and non-hemolytic [16], causing no adverse effects on implanted tissues. This biomaterial can be designed to encapsulate drugs or molecules. The advantages of the encapsulation of therapeutic chemicals are obvious, including stabilizing the drugs that may have a short half-life, enabling the controlled release of therapeutic factors, limiting additional damages to healthy tissues and reducing side effects [6567]. A number of biomaterials have been explored for the repair of ischemic lesion in animal models (Table 2). Here, we will explore these biomaterial-based therapies for stroke with the emphasis on the materials.

Table 2 Biomaterials used in the treatment of stroke


Owing to versatile forms and composition, polymer-based hydrogels have been widely used in many fields, including neural tissue engineering [16, 7678]. Hydrogels are polymeric materials with high water content (i.e. >90% water) and diverse physical properties [79]. Hyaluronan/methyl cellulose (HAMC), an injectable hydrogel, has been used to achieve a short-term controlled delivery of erythropoietin (EPO) in the stroke treatment [73]. The local release of EPO from this HAMC was found to promote endogenous neurogenesis of the SVZ and tissue repair after stroke injury in the mouse brain.


Alginate is naturally derived polysaccharides from brown algae [80] and has been extensively used as hydrogel synthetic extracellular matrix (ECM) [8184]. As a biomaterial, alginate is applied in pharmaceutical industry due to its mechanical and chemical stability and high biocompatibility [85].The utilization of an alginate hydrogel encapsulating VEGF was shown to induce structural and functional protection from ischemic stroke damage in the rat MCAO model [72].


Collagen, the main component of the extracellular matrix, can provide a proper surface for cell adhesion and migration [86]. Because of its advantages in biological compatibility, mechanical strength, degradability and immunogenicity [87, 88], collagen has been widely used in biomedical applications, including stroke treatment. A hyaluronan-heparin-collagen hydrogel seeded with stem cells was transplanted into the infarct cavity after stroke, leading to improved stem cell survival and reduced damage to the brain tissue [71]. When collagen type I and NSCs were combined and transplanted in vivo to treat cerebral ischemic injury, NSCs were found to differentiate and form new synapses. This treatment promoted the structural and functional repair of brain tissue following ischemic stroke [70].


Poly (D, L-lactic acid-co-glycolic acid)(PLGA) is a fully degradable biomaterial with the end products, CO2 and H2O [89]. PLGA particles can be readily obtained using a single oil-in-water emulsion technique. PLGA scafolds can act as a structural support for neural stem cells to enhance brain repair [90]. The implantation of PLGA particles into the brain does not induce adverse host cell responses, such as glial scar and inflammation [89], indicating the excellent biocompatibility of PLGA.

PLGA particles have been used as a vehicle for delivering a number of therapeutic factors for stroke treatment, for instance, PLGA-PEG encapsulating T3 (thyroid hormone) [69]. This PLGA-based treatment led to a decrease in tissue infarction and brain edema. In another stroke treatment, pegylated EGF (PEG-EGF) and EPO were loaded in PLGA nanoparticles and biphasic microparticles (a PLGA core and a poly(sebacic acid) shell), respectively, which were dispersed in an HAMC) hydrogel. This drug delivery system reduced the inflammatory responses and significantly improved neurogenesis [68]. In addition to carrying cytokines, PLGA particles can also be used to deliver stem cells for the therapeutic purpose. hNSCs were seeded onto VEGF-releasing PLGA particles. This cell-cytokine-biomaterial system was found to attract host endothelial cells and promote the development of a local vascular network [22].

Neuro-protective factors

A wide range of neuro-protective factors, including BDNF, GDNF, EPO and NGF (Table 3), have been utilized in treating stroke in animal models [73, 91, 92]. These neuro-protective factors can promote neurogenesis mediated by endogenous NPCs and the survival, proliferation and differentiation of transplanted neural cells [9396]. Thus, these factors play a critical role in stroke treatment.

Table 3 Neuro-protective factors used in the treatment of stroke


Brain-derived neurotrophic factor (BDNF), a secreted neurotrophin, regulates neuronal survival, migration, differentiation and synaptic function [114, 115] by binding to the tropomyosin receptor kinase B (TrkB) [116]. BDNF/TrkB signaling modulates synaptic strength and supports the survival of cortical neurons [63, 117, 118]. A number of studies have investigated the therapeutic effects of BDNF on stroke [91, 97, 119]. The different delivery methods appear to influence different aspects of the therapeutic effects of BDNF. Delivering BDNF intraventricularly reduced infarct size after focal cerebral ischemia in rats [97, 119]. In contrast, the intravenous administration of BDNF did not reduce the final infarct size, but greatly improved motor recovery and induced widespread neuronal remodeling [91]. Moreover, BDNF was also reported to protect brain tissues from ischemic injury [120].


Glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor super-family named transforming growth factor-β (TGF-β) [121], is thought to be the most potent motor neurotrophic factor. It promotes neuronal survival and regulates migration and differentiation of several different types of peripheral neurons [98104], including spinal motor neurons [122] and brain noradrenergic neurons [121]. When treated with GDNF, the infarct size and brain edema in the MCAO rats were significantly reduced [123].


Erythropoietin (EPO), a hematopoietic cytokine [73], promotes the differentiation and proliferation of erythroid progenitor cells and improves the survival of maturing cells [105]. The treatment with recombinant human erythropoietin (rhEPO) after stroke significantly improves functional recovery and enhances angiogenesis and neurogenesis [106]. Furthermore, EPO treatment also provides neuro-protection after brain injury by decreasing the neuronal apoptosis [105]. An HAMC hydrogel encapsulating EPO decreased neuronal apoptosis and reduced stroke cavity size in the mouse brain after stroke injury [73], possibly due to attenuated inflammatory responses and enhanced neurogenesis.


Nerve growth factor (NGF), a member of neurotrophin family, supports the growth and survival of neural cells [124]. Since it was first discovered in 1950, NGF has been explored in the regulation of developing neurological system [125]. Additionally, it also promotes the differentiation of stem cells into neurons and the migration of newly differentiated neurons [126, 127]. NGF mediates neuroprotection through proline-rich Akt substrate (PRAS) phosphorylation and its interaction with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide (YWHAQ) and phosphory-lated Akt (pAkt) [113]. Several studies have investigated the effects of NGF on stroke. The transplantation of bone mesenchymal stem cells (BMSCs) with NGF via the tail vein in MCAO rats was found to improve neurological function and promote the differentiation of BMSCs [124]. Moreover, the intranasal administration of NGF in rat MCAO model improved neurological function with a significant reduction in the infarct volume and enhancement in survival and proliferation of progenitor cells [128].

Design considerations for tissue engineering approach

The engineered scaffolds can be rationally designed to fulfill different regeneration requirements for different tissues or organs. For effectively treating stroke, some general criteria need to be met when one chooses a biomaterial. First of all, an ideal scaffold biomaterial for stroke tissue regeneration should bear a three-dimensional structure that provides a highly biocompatible microenvironment favoring cell growth, adhesion, migration, proliferation and differentiation without eliciting inflammatory responses in vivo [17]. Second, the sufficient number of appropriate cells are required to initiate regeneration and repopulate the affected neuronal tissue towards function restoration. Third, a key aspect for functional replacement of damaged brain tissue is to control the differentiation of transplanted cells into desired phenotypes and guide their integration with the host parenchyma to replace and replenish the damaged neuronal population. This can be achieved through the use of appropriate growth factors. Thus, the biomaterial is required to be able to carry and release these factors in vivo, which should be realized in a controlled manner as the controlled release has been proven to enhance therapeutic effects.

More importantly, by modifying physical and chemical traits of the biomaterial, the engineered scaffold can be designed to possess diverse unique properties. For example, the dynamics of scaffold biodegradation can be programmed to synchronize with the host healing process [129]. Degradable scaffolds can serve as a temporary delivering vehicle for cells and growth factors while avoiding the chronic problems caused by long-term biomaterial implantation. Scaffolds can be designed to acquire the shape-memory property [129] that allows the scaffolds to be transplanted through a minimally invasive approach. Fine modulations of chemical composition of a scaffold can achieve controlled release of the drugs encapsulated within the scaffold in vivo, which would enhance the therapeutic effects of these drugs. When such scaffolds are integrated with cell and cytokine therapies, their unique properties would help to overcome the inherent limitations of these therapies. Additionally, when one designs a scaffold-based tissue engineering strategy, the host immune response to the scaffold, host tissue microenvironment, such as local angiogenesis and vascularization, should be also taken into consideration. Combining these design considerations into scaffold fabrication would maximize the advantages of the tissue engineering approach for stroke treatment.


The need to develop effective therapeutic approaches for the treatment of stroke is compelling. However, to structurally and functionally restore the damage caused by ischemic stroke remains challenging in part because the brain is the most complex organ [44].

Owing to its powerful potential in facilitating tissue regeneration, the tissue engineering based strategy is becoming another promising approach for ischemic stroke treatment. A number of different types of stem cells, including embryonic stem (ES) cells, iPS cells and NSCs, have been utilized in cell therapy to repair the injured brain tissue [90]. One of the major problems associated with this approach is poor cell survival. We believe that with the aid of appropriate scaffolds as carriers for cells, cell survival will be greatly improved in vitro and in vivo.

Some biomaterial scaffolds have been examined in stroke regeneration, such as collagen, hyaluronan, matrige, laminin and nanomaterials (Table 2) [16]. The results indicate biomaterial scaffolds hold promise for promoting structural and functional restoration of stroke-damaged neuronal tissue.

Growths factors have been applied in stroke regeneration such as BDNF, GDNF and EPO [73, 95, 97]. These growth factors can reduce the volume of infarct areas and induce stem cell differentiation (Table 3). However, the intravenous administration often results in a therapeutic effect that is rather transient and inefficient, because some growth factors cannot effectively pass through the blood brain barrier. Localized and sustained release of growths factors or therapeutic factors via scaffolds can be a solution to this problem.

Meanwhile, alternative sources of cells and new combinations of neuro-protective factors should be explored. Advances in development of new scaffold materials may bring tissue engineering treatment one step closer to clinical applications.

Taken together, the tissue-engineering strategy complements cell and cytokine therapies. The combination of both can be a valuable alternative for the clinical treatment of ischemic stroke.



tissue-type plasminogen activator


Neural stem cells


Central nervous system


Subventricular zone


Middle cerebral artery occlusion


human neural stem cells


mesenchymal stem cells


Fibroblast growth factor-2


Epidermal growth factor


Brain-derived neurotrophic factor


Glial fibrillary acidic protein


Subgranular zones


induced pluripotent stem


Hyaluronan/methyl cellulose




Nerve growth factor


Proline-rich Akt substrate


tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptide


phosphory-lated Akt


Extracellular matrix


Poly (D, L-lactic acid-co-glycolic acid)


Endothelial cells


Neural progenitor cells


Glial cell line-derived neurotrophic factor


recombinant human erythropoietin


Embryonic stem


Transforming growth factor-β


Tropomyosin receptor kinase B.


  1. 1.

    Delcroix GJ, Schiller PC, Benoit JP, Montero-Menei CN: Adult cell therapy for brain neuronal damages and the role of tissue engineering. Biomaterials 2010, 31: 2105–2120. 10.1016/j.biomaterials.2009.11.084

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA: Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke; A J Cereb Circ 2001, 32: 1732–1738. 10.1161/01.STR.32.8.1732

    CAS  Article  Google Scholar 

  3. 3.

    Bani-Yaghoub M, Tremblay RG, Ajji A, Nzau M, Gangaraju S, Chitty D, Zurakowski B, Sikorska M: Neuroregenerative strategies in the brain: emerging significance of bone morphogenetic protein 7 (BMP7). Biochem Cell Biol 2008, 86: 361–369. 10.1139/O08-116

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Dimyan MA, Cohen LG: Neuroplasticity in the context of motor rehabilitation after stroke. Nat Rev Neurol 2011, 7: 76–85. 10.1038/nrneurol.2010.200

    PubMed  Article  Google Scholar 

  5. 5.

    Wen H, Dou Z, Finni T, Havu M, Kang Z, Cheng S, Sipila S, Sinha S, Usenius JP: Thigh muscle function in stroke patients revealed by velocity-encoded cine phase-contrast magnetic resonance imaging. Muscle Nerve 2008, 37: 736–744. 10.1002/mus.20986

    PubMed  Article  Google Scholar 

  6. 6.

    Gurgo RD, Bedi KS, Nurcombe V: Current concepts in central nervous system regeneration. J Clin Neurosci 2002, 9: 613–617. 10.1054/jocn.2002.1080

    PubMed  Article  Google Scholar 

  7. 7.

    Case LC, Tessier-Lavigne M: Regeneration of the adult central nervous system. Current Biology : CB 2005, 15: R749–753.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM: Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001, 56: 1015–1020. 10.1212/WNL.56.8.1015

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Killer M, Ladurner G, Kunz AB, Kraus J: Current endovascular treatment of acute stroke and future aspects. Drug Discov Today 2010, 15: 640–647. 10.1016/j.drudis.2010.04.007

    PubMed  Article  Google Scholar 

  10. 10.

    Green AR, Shuaib A: Therapeutic strategies for the treatment of stroke. Drug Discov Today 2006, 11: 681–693. 10.1016/j.drudis.2006.06.001

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Nudo RJ, Plautz EJ, Frost SB: Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve 2001, 24: 1000–1019. 10.1002/mus.1104

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Nudo RJ, Wise BM, SiFuentes F, Milliken GW: Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996, 272: 1791–1794. 10.1126/science.272.5269.1791

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, et al.: Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009, 119: 480–486.

    PubMed  Article  Google Scholar 

  14. 14.

    Kozlowski DA, James DC, Schallert T: Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996, 16: 4776–4786.

    CAS  PubMed  Google Scholar 

  15. 15.

    Bland ST, Pillai RN, Aronowski J, Grotta JC, Schallert T: Early overuse and disuse of the affected forelimb after moderately severe intraluminal suture occlusion of the middle cerebral artery in rats. Behav Brain Res 2001, 126: 33–41. 10.1016/S0166-4328(01)00243-1

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Bhatia SK: Tissue engineering for clinical applications. Biotechnol J 2010, 5: 1309–1323. 10.1002/biot.201000230

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Ozawa T, Mickle DA, Weisel RD, Koyama N, Ozawa S, Li RK: Optimal biomaterial for creation of autologous cardiac grafts. Circulation 2002, 106: I176–182.

    PubMed  Google Scholar 

  18. 18.

    Borlongan CV, Tajima Y, Trojanowski JQ, Lee VM, Sanberg PR: Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats. Exp Neurol 1998, 149: 310–321. 10.1006/exnr.1997.6730

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, Jannetta P, DeCesare S, Elder EM, McGrogan M, et al.: Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000, 55: 565–569. 10.1212/WNL.55.4.565

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC, Masel J, Yenari MA, Weissman IL, Uchida N, et al.: Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci U S A 2004, 101: 11839–11844. 10.1073/pnas.0404474101

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. 21.

    Wieloch T, Nikolich K: Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol 2006, 16: 258–264. 10.1016/j.conb.2006.05.011

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Bible E, Qutachi O, Chau DY, Alexander MR, Shakesheff KM, Modo M: Neo-vascularization of the stroke cavity by implantation of human neural stem cells on VEGF-releasing PLGA microparticles. Biomaterials 2012, 33: 7435–7446. 10.1016/j.biomaterials.2012.06.085

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  23. 23.

    Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD: I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 2005, 136: 161–169. 10.1016/j.neuroscience.2005.06.062

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. 24.

    Palmer TD, Takahashi J, Gage FH: The adult rat hippocampus contains primordial neural stem cells. Mole Cell Neurosci 1997, 8: 389–404. 10.1006/mcne.1996.0595

    CAS  Article  Google Scholar 

  25. 25.

    Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992, 255: 1707–1710. 10.1126/science.1553558

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Tropepe V, Coles BL, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, van der Kooy D: Retinal stem cells in the adult mammalian eye. Science 2000, 287: 2032–2036. 10.1126/science.287.5460.2032

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds BA: Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 1996, 16: 7599–7609.

    CAS  PubMed  Google Scholar 

  28. 28.

    Yu F, Morshead CM: Adult stem cells and bioengineering strategies for the treatment of cerebral ischemic stroke. Curr Stem Cell Res & Therapy 2011, 6: 190–207. 10.2174/157488811796575341

    CAS  Article  Google Scholar 

  29. 29.

    Toda H, Takahashi J, Iwakami N, Kimura T, Hoki S, Mozumi-Kitamura K, Ono S, Hashimoto N: Grafting neural stem cells improved the impaired spatial recognition in ischemic rats. Neurosci Lett 2001, 316: 9–12. 10.1016/S0304-3940(01)02331-X

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Daadi MM, Hu S, Klausner J, Li Z, Sofilos M, Sun G, Wu JC, Steinberg GK: Imaging neural stem cell graft-induced structural repair in stroke. Cell Transplant 2013, 22: 881–892. 10.3727/096368912X656144

    PubMed  Article  Google Scholar 

  31. 31.

    Vaananen HK: Mesenchymal stem cells. Ann Med 2005, 37: 469–479. 10.1080/07853890500371957

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Woodbury D, Schwarz EJ, Prockop DJ, Black IB: Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000, 61: 364–370. 10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M: Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 2001, 189: 49–57. 10.1016/S0022-510X(01)00557-3

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M: Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 2007, 27: 6–13. 10.1038/sj.jcbfm.9600311

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Kocsis JD, Lankford KL, Sasaki M, Radtke C: Unique in vivo properties of olfactory ensheathing cells that may contribute to neural repair and protection following spinal cord injury. Neurosci Lett 2009, 456: 137–142. 10.1016/j.neulet.2008.08.093

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. 36.

    Iwatsuki K, Yoshimine T, Kishima H, Aoki M, Yoshimura K, Ishihara M, Ohnishi Y, Lima C: Transplantation of olfactory mucosa following spinal cord injury promotes recovery in rats. Neuroreport 2008, 19: 1249–1252. 10.1097/WNR.0b013e328305b70b

    PubMed  Article  Google Scholar 

  37. 37.

    Radtke C, Sasaki M, Lankford KL, Vogt PM, Kocsis JD: Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury. J Rehabil Res Dev 2008, 45: 141–151. 10.1682/JRRD.2007.03.0049

    PubMed  Article  Google Scholar 

  38. 38.

    Chiu SC, Hung HS, Lin SZ, Chiang E, Liu DD: Therapeutic potential of olfactory ensheathing cells in neurodegenerative diseases. J Mol Med (Berl) 2009, 87: 1179–1189. 10.1007/s00109-009-0528-2

    Article  Google Scholar 

  39. 39.

    Shyu WC, Liu DD, Lin SZ, Li WW, Su CY, Chang YC, Wang HJ, Wang HW, Tsai CH, Li H: Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. J Clin Invest 2008, 118: 2482–2495. 10.1172/JCI34363

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. 40.

    Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S: Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 2008, 26: 1787–1795. 10.1634/stemcells.2007-0979

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Arthur A, Shi S, Zannettino AC, Fujii N, Gronthos S, Koblar SA: Implanted adult human dental pulp stem cells induce endogenous axon guidance. Stem Cells 2009, 27: 2229–2237. 10.1002/stem.138

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Yalvac ME, Rizvanov AA, Kilic E, Sahin F, Mukhamedyarov MA, Islamov RR, Palotas A: Potential role of dental stem cells in the cellular therapy of cerebral ischemia. Curr Pharm Des 2009, 15: 3908–3916. 10.2174/138161209789649439

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Yang KL, Chen MF, Liao CH, Pang CY, Lin PY: A simple and efficient method for generating Nurr1-positive neuronal stem cells from human wisdom teeth (tNSC) and the potential of tNSC for stroke therapy. Cytotherapy 2009, 11: 606–617. 10.1080/14653240902806994

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Thwaites JW, Reebye V, Mintz P, Levicar N, Habib N: Cellular replacement and regenerative medicine therapies in ischemic stroke. Regen Med 2012, 7: 387–395. 10.2217/rme.12.2

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Darsalia V, Kallur T, Kokaia Z: Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur J Neurosci 2007, 26: 605–614. 10.1111/j.1460-9568.2007.05702.x

    PubMed  Article  Google Scholar 

  46. 46.

    Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO, Maisel M, Lerche H, Schwarz J, Brenner R, Storch A: Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004, 117: 4411–4422. 10.1242/jcs.01307

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Gorski JA, Zeiler SR, Tamowski S, Jones KR: Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 2003, 23: 6856–6865.

    CAS  PubMed  Google Scholar 

  48. 48.

    Maden M: Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 2007, 8: 755–765. 10.1038/nrn2212

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Mezey E: Bone marrow-derived stem cells in neurological diseases: stones or masons? Regen Med 2007, 2: 37–49. 10.2217/17460751.2.1.37

    PubMed  Article  Google Scholar 

  50. 50.

    Bang OY, Lee JS, Lee PH, Lee G: Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005, 57: 874–882. 10.1002/ana.20501

    PubMed  Article  Google Scholar 

  51. 51.

    Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, collaborators S: A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010, 28: 1099–1106. 10.1002/stem.430

    PubMed  Article  Google Scholar 

  52. 52.

    Gilman S: Pharmacologic management of ischemic stroke: relevance to stem cell therapy. Exp Neurol 2006, 199: 28–36. 10.1016/j.expneurol.2006.03.002

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Greenberg DA, Jin K: Turning neurogenesis up a Notch. Nat Med 2006, 12: 884–885. 10.1038/nm0806-884

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA: Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 2001, 98: 4710–4715. 10.1073/pnas.081011098

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  55. 55.

    Kokaia Z, Thored P, Arvidsson A, Lindvall O: Regulation of stroke-induced neurogenesis in adult brain–recent scientific progress. Cereb Cortex 2006,16(Suppl 1):i162–167.

    PubMed  Article  Google Scholar 

  56. 56.

    Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T, Hirota Y, Kawase T, et al.: Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 2006, 26: 6627–6636. 10.1523/JNEUROSCI.0149-06.2006

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Curtis MA, Low VF, Faull RL: Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal and subventricular progenitor proliferation. Dev Neurobiol 2012, 72: 990–1005. 10.1002/dneu.22028

    PubMed  Article  Google Scholar 

  58. 58.

    Carlen M, Meletis K, Goritz C, Darsalia V, Evergren E, Tanigaki K, Amendola M, Barnabe-Heider F, Yeung MS, Naldini L, et al.: Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci 2009, 12: 259–267. 10.1038/nn.2268

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Guan J, Tong W, Ding W, Du S, Xiao Z, Han Q, Zhu Z, Bao X, Shi X, Wu C, et al.: Neuronal regeneration and protection by collagen-binding BDNF in the rat middle cerebral artery occlusion model. Biomaterials 2012, 33: 1386–1395. 10.1016/j.biomaterials.2011.10.073

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131: 861–872. 10.1016/j.cell.2007.11.019

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Chen SJ, Chang CM, Tsai SK, Chang YL, Chou SJ, Huang SS, Tai LK, Chen YC, Ku HH, Li HY, Chiou SH: Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue. Stem Cells Dev 2010, 19: 1757–1767. 10.1089/scd.2009.0452

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, Ikeda Y, Matsuura T, Abe K: Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab 2010, 30: 1487–1493. 10.1038/jcbfm.2010.32

    PubMed Central  PubMed  Article  Google Scholar 

  63. 63.

    Alcantara S, Frisen J, del Rio JA, Soriano E, Barbacid M, Silos-Santiago I: TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J Neurosci 1997, 17: 3623–3633.

    CAS  PubMed  Google Scholar 

  64. 64.

    Greenwood HL, Singer PA, Downey GP, Martin DK, Thorsteinsdottir H, Daar AS: Regenerative medicine and the developing world. PLoS Med 2006, 3: e381. 10.1371/journal.pmed.0030381

    PubMed Central  PubMed  Article  Google Scholar 

  65. 65.

    Brem H: Polymers to treat brain tumours. Biomaterials 1990, 11: 699–701. 10.1016/0142-9612(90)90030-T

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Brem H, Gabikian P: Biodegradable polymer implants to treat brain tumors. J Control Release 2001, 74: 63–67. 10.1016/S0168-3659(01)00311-X

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Panigrahi M, Das PK, Parikh PM: Brain tumor and Gliadel wafer treatment. Indian J Cancer 2011, 48: 11–17. 10.4103/0019-509X.76623

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Wang Y, Cooke MJ, Sachewsky N, Morshead CM, Shoichet MS: Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke. J Control Release 2013, 172: 1–11. 10.1016/j.jconrel.2013.07.032

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Mdzinarishvili A, Sutariya V, Talasila PK, Geldenhuys WJ, Sadana P: Engineering triiodothyronine (T3) nanoparticle for use in ischemic brain stroke. Drug Delivery Transl Res 2013, 3: 309–317. 10.1007/s13346-012-0117-8

    CAS  Article  Google Scholar 

  70. 70.

    Yu H, Cao B, Feng M, Zhou Q, Sun X, Wu S, Jin S, Liu H, Lianhong J: Combinated transplantation of neural stem cells and collagen type I promote functional recovery after cerebral ischemia in rats. Anat Rec (Hoboken) 2010, 293: 911–917. 10.1002/ar.20941

    Article  Google Scholar 

  71. 71.

    Zhong J, Chan A, Morad L, Kornblum HI, Fan G, Carmichael ST: Hydrogel matrix to support stem cell survival after brain transplantation in stroke. Neurorehabil Neural Repair 2010, 24: 636–644. 10.1177/1545968310361958

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Emerich DF, Silva E, Ali O, Mooney D, Bell W, Yu SJ, Kaneko Y, Borlongan C: Injectable VEGF hydrogels produce near complete neurological and anatomical protection following cerebral ischemia in rats. Cell Transplant 2010, 19: 1063–1071. 10.3727/096368910X498278

    PubMed  Article  Google Scholar 

  73. 73.

    Wang Y, Cooke MJ, Morshead CM, Shoichet MS: Hydrogel delivery of erythropoietin to the brain for endogenous stem cell stimulation after stroke injury. Biomaterials 2012, 33: 2681–2692. 10.1016/j.biomaterials.2011.12.031

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Ma J, Tian WM, Hou SP, Xu QY, Spector M, Cui FZ: An experimental test of stroke recovery by implanting a hyaluronic acid hydrogel carrying a Nogo receptor antibody in a rat model. Biomed Mater 2007, 2: 233–240. 10.1088/1748-6041/2/4/005

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Park KI, Teng YD, Snyder EY: The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol 2002, 20: 1111–1117. 10.1038/nbt751

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Place ES, George JH, Williams CK, Stevens MM: Synthetic polymer scaffolds for tissue engineering. Chem Soc Rev 2009, 38: 1139–1151. 10.1039/b811392k

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Hunt NC, Grover LM: Cell encapsulation using biopolymer gels for regenerative medicine. Biotechnol Lett 2010, 32: 733–742. 10.1007/s10529-010-0221-0

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Perale G, Rossi F, Sundstrom E, Bacchiega S, Masi M, Forloni G, Veglianese P: Hydrogels in spinal cord injury repair strategies. ACS Chem Neurosci 2011, 2: 336–345. 10.1021/cn200030w

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  79. 79.

    Seliktar D: Designing cell-compatible hydrogels for biomedical applications. Science 2012, 336: 1124–1128. 10.1126/science.1214804

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Augst AD, Kong HJ, Mooney DJ: Alginate hydrogels as biomaterials. Macromol Biosci 2006, 6: 623–633. 10.1002/mabi.200600069

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Crooks CA, Douglas JA, Broughton RL, Sefton MV: Microencapsulation of mammalian cells in a HEMA-MMA copolymer: effects on capsule morphology and permeability. J Biomed Mater Res 1990, 24: 1241–1262. 10.1002/jbm.820240908

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Lim F, Sun AM: Microencapsulated islets as bioartificial endocrine pancreas. Science 1980, 210: 908–910. 10.1126/science.6776628

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Atala A, Kim W, Paige KT, Vacanti CA, Retik AB: Endoscopic treatment of vesicoureteral reflux with a chondrocyte-alginate suspension. J Urol 1994, 152: 641–643. discussion 644

    CAS  PubMed  Google Scholar 

  84. 84.

    Jen AC, Wake MC, Mikos AG: Review: hydrogels for cell immobilization. Biotechnol Bioeng 1996, 50: 357–364. 10.1002/(SICI)1097-0290(19960520)50:4<357::AID-BIT2>3.3.CO;2-F

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Klock G, Pfeffermann A, Ryser C, Grohn P, Kuttler B, Hahn HJ, Zimmermann U: Biocompatibility of mannuronic acid-rich alginates. Biomaterials 1997, 18: 707–713. 10.1016/S0142-9612(96)00204-9

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Egeblad M, Rasch MG, Weaver VM: Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 2010, 22: 697–706. 10.1016/

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  87. 87.

    O'Connor SM, Andreadis JD, Shaffer KM, Ma W, Pancrazio JJ, Stenger DA: Immobilization of neural cells in three-dimensional matrices for biosensor applications. Biosens Bioelectron 2000, 14: 871–881. 10.1016/S0956-5663(99)00055-X

    PubMed  Article  Google Scholar 

  88. 88.

    Cross VL, Zheng Y, Won Choi N, Verbridge SS, Sutermaster BA, Bonassar LJ, Fischbach C, Stroock AD: Dense type I collagen matrices that support cellular remodeling and microfabrication for studies of tumor angiogenesis and vasculogenesis in vitro. Biomaterials 2010, 31: 8596–8607. 10.1016/j.biomaterials.2010.07.072

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  89. 89.

    Menei P, Montero-Menei C, Venier MC, Benoit JP: Drug delivery into the brain using poly(lactide-co-glycolide) microspheres. Expert Opin Drug Deliv 2005, 2: 363–376. 10.1517/17425247.2.2.363

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Bible E, Chau DY, Alexander MR, Price J, Shakesheff KM, Modo M: The support of neural stem cells transplanted into stroke-induced brain cavities by PLGA particles. Biomaterials 2009, 30: 2985–2994. 10.1016/j.biomaterials.2009.02.012

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Schabitz WR, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, Schwab S, Sommer C: Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke 2004, 35: 992–997. 10.1161/01.STR.0000119754.85848.0D

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Shang J, Deguchi K, Yamashita T, Ohta Y, Zhang H, Morimoto N, Liu N, Zhang X, Tian F, Matsuura T, et al.: Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. J Neurosci Res 2010, 88: 2197–2206. 10.1002/jnr.22373

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Jin KL, Mao XO, Greenberg DA: Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci U S A 2000, 97: 10242–10247. 10.1073/pnas.97.18.10242

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  94. 94.

    Shingo T, Sorokan ST, Shimazaki T, Weiss S: Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 2001, 21: 9733–9743.

    CAS  PubMed  Google Scholar 

  95. 95.

    Duarte EP, Curcio M, Canzoniero LM, Duarte CB: Neuroprotection by GDNF in the ischemic brain. Growth Factors 2012, 30: 242–257. 10.3109/08977194.2012.691478

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, Katakowski M, Lu M, Chopp M: Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 2005, 25: 281–290. 10.1038/sj.jcbfm.9600034

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  97. 97.

    Schabitz WR, Schwab S, Spranger M, Hacke W: Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1997, 17: 500–506.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Trupp M, Ryden M, Jornvall H, Funakoshi H, Timmusk T, Arenas E, Ibanez CF: Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J Cell Biol 1995, 130: 137–148. 10.1083/jcb.130.1.137

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Airaksinen MS, Saarma M: The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002, 3: 383–394. 10.1038/nrn812

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Sariola H, Saarma M: Novel functions and signalling pathways for GDNF. J Cell Sci 2003, 116: 3855–3862. 10.1242/jcs.00786

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Enomoto H: Regulation of neural development by glial cell line-derived neurotrophic factor family ligands. Anat Sci Int 2005, 80: 42–52. 10.1111/j.1447-073x.2005.00099.x

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Paratcha G, Ledda F: GDNF and GFRalpha: a versatile molecular complex for developing neurons. Trends Neurosci 2008, 31: 384–391. 10.1016/j.tins.2008.05.003

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Arenas E, Trupp M, Akerud P, Ibanez CF: GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron 1995, 15: 1465–1473. 10.1016/0896-6273(95)90024-1

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Ibanez CF: Beyond the cell surface: new mechanisms of receptor function. Biochem Biophys Res Commun 2010, 396: 24–27. 10.1016/j.bbrc.2010.01.136

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, et al.: Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 2001, 98: 4044–4049. 10.1073/pnas.051606598

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  106. 106.

    Wang L, Zhang Z, Wang Y, Zhang R, Chopp M: Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004, 35: 1732–1737. 10.1161/01.STR.0000132196.49028.a4

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Belayev L, Khoutorova L, Zhao KL, Davidoff AW, Moore AF, Cramer SC: A novel neurotrophic therapeutic strategy for experimental stroke. Brain Res 2009, 1280: 117–123.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Kolb B, Morshead C, Gonzalez C, Kim M, Gregg C, Shingo T, Weiss S: Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 2007, 27: 983–997.

    CAS  PubMed  Google Scholar 

  109. 109.

    Won SJ, Xie L, Kim SH, Tang H, Wang Y, Mao X, Banwait S, Jin K: Influence of age on the response to fibroblast growth factor-2 treatment in a rat model of stroke. Brain Res 2006, 1123: 237–244. 10.1016/j.brainres.2006.09.055

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  110. 110.

    Hayon Y, Dashevsky O, Shai E, Varon D, Leker RR: Platelet lysates stimulate angiogenesis, neurogenesis and neuroprotection after stroke. Thromb Haemost 2013, 110: 323–330. 10.1160/TH12-11-0875

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Guerra-Crespo M, Gleason D, Sistos A, Toosky T, Solaroglu I, Zhang JH, Bryant PJ, Fallon JH: Transforming growth factor-alpha induces neurogenesis and behavioral improvement in a chronic stroke model. Neuroscience 2009, 160: 470–483. 10.1016/j.neuroscience.2009.02.029

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Han JL, Blank T, Schwab S, Kollmar R: Inhibited glutamate release by granulocyte-colony stimulating factor after experimental stroke. Neurosci Lett 2008, 432: 167–169. 10.1016/j.neulet.2007.07.056

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Saito A, Narasimhan P, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH: Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: relationships with nerve growth factor. J Neurosci 2004, 24: 1584–1593. 10.1523/JNEUROSCI.5209-03.2004

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Bibel M, Barde YA: Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000, 14: 2919–2937. 10.1101/gad.841400

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Huang EJ, Reichardt LF: Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001, 24: 677–736. 10.1146/annurev.neuro.24.1.677

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  116. 116.

    Miller FD, Kaplan DR: Neurotrophin signalling pathways regulating neuronal apoptosis. Cell Mol Life Sci 2001, 58: 1045–1053. 10.1007/PL00000919

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Poo MM: Neurotrophins as synaptic modulators. Nat Rev Neurosci 2001, 2: 24–32. 10.1038/35049004

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Ghosh A, Carnahan J, Greenberg ME: Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994, 263: 1618–1623. 10.1126/science.7907431

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Yamashita K, Wiessner C, Lindholm D, Thoenen H, Hossmann KA: Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis 1997, 12: 271–280.

    CAS  PubMed  Google Scholar 

  120. 120.

    Jiang Y, Wei N, Zhu J, Lu T, Chen Z, Xu G, Liu X: Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat. Mediators Inflamm 2010, 2010: 372423.

    PubMed Central  PubMed  Google Scholar 

  121. 121.

    Lin LF, Zhang TJ, Collins F, Armes LG: Purification and initial characterization of rat B49 glial cell line-derived neurotrophic factor. J Neurochem 1994, 63: 758–768.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Henderson CE, Phillips HS, Pollock RA, Davies AM, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen RA, Simpson LC, et al.: GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 1994, 266: 1062–1064. 10.1126/science.7973664

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Kitagawa H, Hayashi T, Mitsumoto Y, Koga N, Itoyama Y, Abe K: Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 1998, 29: 1417–1422. 10.1161/01.STR.29.7.1417

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Ding J, Cheng Y, Gao S, Chen J: Effects of nerve growth factor and Noggin-modified bone marrow stromal cells on stroke in rats. J Neurosci Res 2011, 89: 222–230. 10.1002/jnr.22535

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Levi-Montalcini R, Calissano P: The nerve-growth factor. Sci Am 1979, 240: 68–77.

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Choi KC, Yoo DS, Cho KS, Huh PW, Kim DS, Park CK: Effect of single growth factor and growth factor combinations on differentiation of neural stem cells. J Korean Neurosurgical Soc 2008, 44: 375–381. 10.3340/jkns.2008.44.6.375

    Article  Google Scholar 

  127. 127.

    Mashayekhi F: Neural cell death is induced by neutralizing antibody to nerve growth factor: an in vivo study. Brain Dev 2008, 30: 112–117. 10.1016/j.braindev.2007.07.001

    PubMed  Article  Google Scholar 

  128. 128.

    Cheng S, Ma M, Ma Y, Wang Z, Xu G, Liu X: Combination therapy with intranasal NGF and electroacupuncture enhanced cell proliferation and survival in rats after stroke. Neurol Res 2009, 31: 753–758. 10.1179/174313209X382557

    PubMed  Article  Google Scholar 

  129. 129.

    Wang L, Shansky J, Borselli C, Mooney D, Vandenburgh H: Design and fabrication of a biodegradable, covalently crosslinked shape-memory alginate scaffold for cell and growth factor delivery. Tissue Eng Part A 2012, 18: 2000–2007. 10.1089/ten.tea.2011.0663

    CAS  PubMed Central  PubMed  Article  Google Scholar 

Download references


This work was supported by the research grants from the National Natural Science Foundation of China (81272559) and the Ministry of Education, Science and Technology Research Project (113044A).

Author information



Corresponding author

Correspondence to Lin Wang.

Additional information

Competing interests

The authors declare no competing financial interests.

Authors’ contribution

JW, WY, H-JX, YS, Y-KL and LW participated in drafting the article. All authors read and approved the final manuscript.

Jian Wang, Wen Yang contributed equally to this work.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Wang, J., Yang, W., Xie, H. et al. Ischemic stroke and repair: current trends in research and tissue engineering treatments. Regen Med Res 2, 3 (2014).

Download citation


  • Ischemic stroke
  • Tissue engineering
  • Biomaterials
  • Neuro-protective factors
  • Cell therapy