Commentary | Open | Published:
A brief perspective on neural cell therapy
Molecular and Cellular Therapiesvolume 2, Article number: 2 (2014)
For a range of nervous system disorders current treatment options remain limited. Focusing on Parkinson’s disease as a neurodegenerative entity that affects an increasing quantity of people in our aging societies, we briefly discuss remaining challenges and opportunities that neural stem cell therapy might be able to offer. Providing a snapshot of neural transplantation paradigms, we contemplate possible imminent translational scenarios and discuss critical requirements to be considered before clinical implementation.
Repairing the central nervous system may appear daunting in light of how little we still understand about its intricate molecular and cellular structure. Nevertheless, concepts of neural cell transplantation were explored early on, and since the 1980s there have been more concentrated systematic efforts in the area of Parkinson’s disease, specifically, which is used here as a salient example (for review, see ) (Figure 1). Its progressive, widespread pathology includes a rather circumscribed epicenter of cell loss: the dopaminergic neurons located in the ventral midbrain which send axonal projections to target cells in the striatum and play a critical role in the control of voluntary movement. Based on a solid fundament of rodent and primate studies, functional replacement of the dopaminergic neuronal subset by engrafting fetal midbrain tissue has been unequivocally demonstrated (for review, see [2, 3]).
This body of work has led to clinical trials (for review and meta-analysis, see ) including double blind, sham-surgery controlled [5, 6] and open-label studies with varying clinical and neuropathological outcomes and assessments [7–9]. The important proof-of-principle, however, that neural cell preparations can survive long-term, restore function and alleviate neurological disease by means of “replacement” was provided by these studies [10, 11]. In addition, cell preparations from various tissues of origin have been used in neural cell therapeutic paradigms, including long term-expanded neural lines, hematopoietic and other mesenchymal-derived sources. The associated disease modulatory effects may carry the potential for medical benefit, and non-neural cells could serve as vehicles for trophic factor release or gene delivery but do not represent cell replacement in the sense of the original ambitions. A number of phase-1 clinical trials have been initiated based on, at least partially, comparably limited sets of pre-clinical data. When considering such paradigms, one critical demand will be that the overall efficacy supersedes that of current standard or alternative experimental therapeutic options (even if the threshold to clinical translation appears somewhat lower due to the perceived “safer” character of such sources [12, 13]). In addition to continuously improving pharmacological therapies (for review, see ), as well as neurostimulatory approaches using electrode implantation (deep brain stimulation) (for review, see ), RNA interference-based approaches that aim for amelioration of disease by preventing formation of the pathognomonic neural protein aggregates, for instance, have to be considered as potentially feasible, promising therapeutic alternatives (for review, see ). Still, the lasting structural and functional repair of neural circuits by means of cell replacement is a worthy goal with potential biomedical benefit beyond what experimental alternatives may offer . To achieve more reliable and predictable outcomes post-transplantation of fetal ventral midbrain tissue for Parkinson’s disease, an ongoing multicenter clinical program aims at fine-tuning and coordinating neural transplantation procedures and protocols . Long-term it is unlikely, as ethically problematic and technically hardly feasible, to consider human fetal neural cell preparations for future clinical routines. What are some concrete milestones to achieve in bringing neural cell replacement to the clinics? Among the most important requirements is the generation of the actual therapeutic agent, i.e. the cell preparation to be administered, and pluripotent sources may provide a scalable and potentially efficacious alternative [19, 20]. It will be critical to specify functional equivalents of the phenotypes in need, and to exclude uncontrolled generation of proliferative or otherwise unwanted subtypes [21, 22]. On a cellular level, this requires the reliable control of gene regulatory networks that define the phenotype of interest , on a biotechnological level the development of reliable, scalable protocols that predictably generate the desired cell type from pluripotent or multipotent sources . Learning from the ontogenic neural stem cell niche, extracellular matrix molecules, growth and patterning factors or small molecule inducers can be applied to generate cells that approximate the physiological equivalent in vitro (for review, see ). A cell source to be applied in a therapeutic context requires an explicit “score card” of characteristics that need to be met (Figure 2), which may include expression of definitive gene loci, transmitter release and electrophysiological activities and surface molecular patterns. The first and the latter can be economically and efficiently tested by implementing customized arrays  and flow cytometric readouts [21, 22] into the cell production routines. Although the central nervous system has been regarded as a somewhat immune privileged site , the immunogenic potential of the cell preparation also needs to be considered . Patient-derived induced-pluripotent stem cell preparations provide options for autologous transplantation, but it remains to be seen whether the complex methodological work-flows (donor cell harvesting, reprogramming, expansion, induction of phenotype, transplantation) could ever be sufficiently economized to make this a clinical reality. Easier to envision is a cell bank with major histocompatibility complex profiles that closely match particular patient subsets . Of equal significance to basic research and biotechnological efforts is the parallel refinement of medical parameters which include the identification of:
The best candidate disease, the most appropriate patient collective and disease stage to intervene, taking into account the conditions of the host/ recipient tissue at the implantation site.
The most appropriate means of delivery and diagnostically conclusive readout assessments.
The means to avoid potential unwanted side-effects and to ensure proper access to follow-up and parallel supportive therapies.
In a nascent journal on Molecular and Cellular Therapies, one may explore opportunities for further innovative developments. Induced pluripotent stem cell technology  and direct phenotype conversion by epigenetic modifications (iN and iNS cells; for review, see ) paired with novel tools for genome editing of human cell lines (for review, see ) make it conceivable that disease correction of such autologous cell sources could efficiently be performed before readministration to the patient. Epigenetic (re)programming will require sophisticated insights into the most appropriate gene expression make-up (dosage and ratios) of the needed phenotype. Moreover, continuous optimization of directed cell differentiation and recent developments in 3D differentiation systems that imitate embryological tissue context may provide an avenue to yield close-to physiological cell types . In terms of delivery, cell administration via the blood stream or cerebrospinal fluid (intrathecally) may eventually complement the current standard neuro-stereotactic approaches. Potentially, one could exploit certain “cellular homing” behavior to a lesion in certain contexts (tumors, inflammation, ischemia). For neurodevelopmental disorders, modes of delivery may include in utero surgery (for review of spina bifida as a clinical example, see ). Finally, an attractive option is to enhance the limited neuroregenerative capacities of the brain itself for intrinsic cell replacement (for review see ). As illustrated by the rapid and unexpected developments in stem cell biology of the past few years and months, predicting the actual biomedical realities may be difficult. More important may be postulating self-imposed, if not regulatory, criteria that could guide future developments:
To remain aware of the considerable responsibilities that come with conducting work (funded) to diminish human suffering caused by disease and the concomitant hopes put into our daily work.
To not compromise on the demand for functional effects and to critically evaluate the need for animal studies before clinical translation (behavioral recovery).
To educate the public, including patients, caretakers and family members as well as organizations (and funding bodies) and moderate their enthusiasm, hope and unjustified expectations, where appropriate.
Adherence to such principles ensures lasting trust toward this field and may avert unwarranted hype, while maintaining the justifiable enthusiasm and motivation that clinicians, physician-scientists and basic researchers working in the fields of regenerative medicine and applied stem cell biology share in terms of bringing the joint scientific efforts to clinical fruition.
As optimized protocols generate increasingly authentic and safer neural cell preparations, future efforts may focus on refining parameters of patient selection and cell delivery. Ultimately, enhanced interdisciplinary dialogue and applying the highest scientific standards on all levels from basic stem cell biology to clinical protocol development may make neural cell restoration via cell therapy a clinical reality.
Politis M, Lindvall O: Clinical application of stem cell therapy in Parkinson’s disease. BMC Med. 2012, 10: 1-10.1186/1741-7015-10-1.
Tsui A, Isacson O: Functions of the nigrostriatal dopaminergic synapse and the use of neurotransplantation in Parkinson’s disease. J Neurol. 2011, 258: 1393-1405. 10.1007/s00415-011-6061-6.
Bjorklund A, Kordower JH: Cell therapy for Parkinson’s disease: what next?. Mov Disord. 2013, 28: 110-115. 10.1002/mds.25343.
Barker RA, Barrett J, Mason SL, Björklund A: Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol. 2013, 12: 84-91. 10.1016/S1474-4422(12)70295-8.
Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001, 344: 710-719. 10.1056/NEJM200103083441002.
Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB: A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003, 54: 403-414. 10.1002/ana.10720.
Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O: Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med. 2008, 14: 507-509. 10.1038/nm1752.
Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P: Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008, 14: 501-503. 10.1038/nm1746.
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008, 14: 504-506. 10.1038/nm1747.
Cooper O, Astradsson A, Hallett P, Robertson H, Mendez I, Isacson O: Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients. J Neurol. 2009, 256 (Suppl 3): 310-316.
Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Oertel WH, Björklund A, Lindvall O, Piccini P: Serotonin neuron loss and nonmotor symptoms continue in Parkinson’s patients treated with dopamine grafts. Sci Transl Med. 2012, 4: 128ra41-
Olanow CW, Isacson O: Stem cells for Parkinson’s disease: advancing science but protecting patients. Mov Disord. 2012, 27: 1475-1477. 10.1002/mds.25170.
Bianco P, Barker R, Brüstle O, Cattaneo E, Clevers H, Daley GQ, De Luca M, Goldstein L, Lindvall O, Mummery C, Robey PG, Sattler De Sousa E, Brito C, Smith A: Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. EMBO J. 2013, 32: 1489-1495. 10.1038/emboj.2013.114.
Smith Y, Wichmann T, Factor SA, DeLong MR: Parkinson’s disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacology. 2012, 37: 213-246. 10.1038/npp.2011.212.
Miocinovic S, Somayajula S, Chitnis S, Vitek JL: History, applications, and mechanisms of deep brain stimulation. JAMA Neurol. 2013, 70: 163-171. 10.1001/2013.jamaneurol.45.
Ramachandran PS, Keiser MS, Davidson BL: Recent advances in RNA interference therapeutics for CNS diseases. Neurotherapeutics. 2013, 10: 473-485. 10.1007/s13311-013-0183-8.
Lindvall O: Developing dopaminergic cell therapy for Parkinson’s disease–give up or move forward?. Mov Disord. 2013, 28: 268-273. 10.1002/mds.25378.
Evans JR, Mason SL, Barker RA: Current status of clinical trials of neural transplantation in Parkinson’s disease. Prog Brain Res. 2012, 200: 169-198.
Murry CE, Keller G: Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008, 132: 661-680. 10.1016/j.cell.2008.02.008.
Ito D, Okano H, Suzuki N: Accelerating progress in induced pluripotent stem cell research for neurological diseases. Ann Neurol. 2012, 72: 167-174. 10.1002/ana.23596.
Turaç G, Hindley CJ, Thomas R, Davis JA, Deleidi M, Gasser T, Karaöz E, Pruszak J: Combined flow cytometric analysis of surface and intracellular antigens reveals surface molecule markers of human neuropoiesis. PLoS One. 2013, 8: e68519-10.1371/journal.pone.0068519.
Yuan SH, Martin J, Elia J, Flippin J, Paramban RI, Hefferan MP, Vidal JG, Mu Y, Killian RL, Israel MA, Emre N, Marsala S, Marsala M, Gage FH, Goldstein LS, Carson CT: Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS One. 2011, 6: e17540-10.1371/journal.pone.0017540.
Pruszak J, Isacson O: Molecular and cellular determinants for generating ES-cell derived dopamine neurons for cell therapy. Adv Exp Med Biol. 2009, 651: 112-123. 10.1007/978-1-4419-0322-8_11.
Kriks S, Studer L: Protocols for generating ES cell-derived dopamine neurons. Adv Exp Med Biol. 2009, 651: 101-111. 10.1007/978-1-4419-0322-8_10.
Solozobova V, Wyvekens N, Pruszak J: Lessons from the embryonic neural stem cell niche for neural lineage differentiation of pluripotent stem cells. Stem Cell Rev. 2012, 8: 813-829. 10.1007/s12015-012-9381-8.
Anisimov SV, Christophersen NS, Correia AS, Li JY, Brundin P: “NeuroStem Chip”: a novel highly specialized tool to study neural differentiation pathways in human stem cells. BMC Genomics. 2007, 8: 46-10.1186/1471-2164-8-46.
Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC: CNS immune privilege: hiding in plain sight. Immunol Rev. 2006, 213: 48-65. 10.1111/j.1600-065X.2006.00441.x.
Zhao T, Zhang ZN, Rong Z, Xu Y: Immunogenicity of induced pluripotent stem cells. Nature. 2011, 474: 212-215. 10.1038/nature10135.
Nakatsuji N, Nakajima F, Tokunaga K: HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008, 26: 739-740. 10.1038/nbt0708-739.
Liu GH, Yi F, Suzuki K, Qu J, Izpisua Belmonte JC: Induced neural stem cells: a new tool for studying neural development and neurological disorders. Cell Res. 2012, 22: 1087-1091. 10.1038/cr.2012.73.
Gaj T, Gersbach CA, Barbas CF: ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 2013, 31: 397-405. 10.1016/j.tibtech.2013.04.004.
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA: Cerebral organoids model human brain development and microcephaly. Nature. 2013, 501: 373-379. 10.1038/nature12517.
Adzick NS: Fetal surgery for spina bifida: past, present, future. Semin Pediatr Surg. 2013, 22: 10-17. 10.1053/j.sempedsurg.2012.10.003.
Bellenchi GC, Volpicelli F, Piscopo V, Perrone-Capano C, Di Porzio U: Adult neural stem cells: an endogenous tool to repair brain injury?. J Neurochem. 2013, 124: 159-167. 10.1111/jnc.12084.
The author’s research program is funded by the German Research Foundation (DFG) grant PR1132/3-1.
The author is a member of the editorial board of Molecular and Cellular Therapies.