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Primary Choroid Plexus Tissue for Use in Cellular Therapy

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Book cover Cell Microencapsulation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1479))

Abstract

The choroid plexus (CP) has been explored as a cellular therapeutic due to its broad-ranging secretome and demonstrated longevity in a variety of encapsulation modalities. While the CP organ is normally involved in disease repair processes in the brain, the range of indications that could potentially be ameliorated with exogenous CP therapy is widespread, including diseases of the central nervous system, hearing loss, chronic wounds, and others. The CP can be isolated from animal sources and digested into a highly purified epithelial culture that can withstand encapsulation and transplantation. Its epithelium can adapt to different microenvironments, and depending on culture conditions, can be manipulated into various three-dimensional configurations with distinct gene expression profiles. The cocktail of proteins secreted by the CP can be harvested in culture, and purified forms of these extracts have been evaluated in topical applications to treat poorly healing wounds. When encapsulated, the epithelial clusters can be maintained for extended durations in vitro with minimal impact on potency. A treatment for Parkinson’s disease utilizing encapsulated porcine CP has been developed and is currently being evaluated in a Phase I clinical trial. The current chapter serves to summarize recent experience with CP factor delivery, and provides a description of the relevant materials and methods employed in these studies.

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References

  1. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4(147):147ra111. doi:10.1126/scitranslmed.3003748

    Article  Google Scholar 

  2. Oshio K, Song Y, Verkman AS, Manley GT (2003) Aquaporin-1 deletion reduces osmotic water permeability and cerebrospinal fluid production. Acta Neurochir Suppl 86:525–528

    CAS  Google Scholar 

  3. Schwerk C, Tenenbaum T, Kim KS, Schroten H (2015) The choroid plexus – a multi-role player during infectious diseases of the CNS. Front Cell Neurosci 9(80):1–11

    Google Scholar 

  4. Dziegielewska KM, Ek J, Habgood MD, Saunders NR (2001) Development of the choroid plexus. Microsc Res Tech 52(1):5–20. doi:10.1002/1097-0029(20010101)52:1<5::AID-JEMT3>3.0.CO;2-J

    Article  CAS  Google Scholar 

  5. Chodobski A, Szmydynger-Chodobska J (2001) Choroid plexus: target for polypeptides and site of their synthesis. Microsc Res Tech 52(1):65–82. doi:10.1002/1097-0029(20010101)52:1<65::AID-JEMT9>3.0.CO;2-4

    Article  CAS  Google Scholar 

  6. Emerich DF, Skinner SJ, Borlongan CV, Vasconcellos AV, Thanos CG (2005) The choroid plexus in the rise, fall and repair of the brain. Bioessays 27(3):262–274

    Article  CAS  Google Scholar 

  7. Thanos CG, Bintz BE, Goddard M, Boekelheide K, Hall S, Emerich DF (2011) Functional modulation of choroid plexus epithelial clusters in vitro for tissue repair applications. Cell Transplant 20(11-12):1659–1672. doi:10.3727/096368911X564985

    Article  CAS  Google Scholar 

  8. ClinicalTrials.gov (2012) Open-label investigation of the safety and clinical effects of NTCELL in patients with Parkinson’s disease. NIH. https://clinicaltrials.gov/ct2/show/NCT01734733. Accessed 15 Sept 2015

  9. Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV, Elliott RB, Emerich DF (2004) Neuroprotection by encapsulated choroid plexus in a rodent model of Huntington’s disease. Neuroreport 15(16):2521–2525

    Article  Google Scholar 

  10. Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV, Elliott RB, Emerich DF (2004) Intracerebral transplantation of porcine choroid plexus provides structural and functional neuroprotection in a rodent model of stroke. Stroke 35(9):2206–2210

    Article  Google Scholar 

  11. Emerich DF, Thanos CG, Goddard MB, Skinner SJ, Geaney M, Bell WJ, Bintz BE, Schneider PA, Chu Y, Babu RS, Borlongan CV, Boekelheide K, Hall S, Bryant B, Kordower JH (2006) Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys. Neurobiol Dis 23(2):471–480

    Article  Google Scholar 

  12. Thanos CG, Emerich DF, Bintz BE, Goddard M, Mills J, Jensen R, Lombardi M, Hall S, Boekelheide K (2009) Secreted products from the porcine choroid plexus accelerate the healing of cutaneous wounds. Cell Transplant 18(12):1395–1409. doi:10.3727/096368909X12483162197402

    Article  CAS  Google Scholar 

  13. Preston JE (2001) Ageing choroid plexus-cerebrospinal fluid system. Microsc Res Tech 52(1):31–37. doi:10.1002/1097-0029(20010101)52:1<31::AID-JEMT5>3.0.CO;2-T

    Article  CAS  Google Scholar 

  14. Serot JM, Bene MC, Foliguet B, Faure GC (2000) Morphological alterations of the choroid plexus in late-onset Alzheimer’s disease. Acta Neuropathol 99(2):105–108

    Article  CAS  Google Scholar 

  15. Wen GY, Wisniewski HM, Kascsak RJ (1999) Biondi ring tangles in the choroid plexus of Alzheimer’s disease and normal aging brains: a quantitative study. Brain Res 832(1-2):40–46

    Article  CAS  Google Scholar 

  16. Emerich DF, Schneider P, Bintz B, Hudak J, Thanos CG (2007) Aging reduces the neuroprotective capacity, VEGF secretion, and metabolic activity of rat choroid plexus epithelial cells. Cell Transplant 16(7):697–705

    Article  Google Scholar 

  17. Wise AK, Fallon JB, Neil AJ, Pettingill LN, Geaney MS, Skinner SJ, Shepherd RK (2011) Combining cell-based therapies and neural prostheses to promote neural survival. Neurotherapeutics 8(4):774–787. doi:10.1007/s13311-011-0070-0

    Article  CAS  Google Scholar 

  18. Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV, Elliott RB, Emerich DF (2004) CNS grafts of rat choroid plexus protect against cerebral ischemia in adult rats. Neuroreport 15(10):1543–1547

    Article  CAS  Google Scholar 

  19. Greenwood S, Swetloff A, Wade AM, Terasaki T, Ferretti P (2008) Fgf2 is expressed in human and murine embryonic choroid plexus and affects choroid plexus epithelial cell behaviour. Cerebrospinal Fluid Res 5(20)

    Google Scholar 

  20. Thouvenot E, Lafon-Cazal M, Demettre E, Jouin P, Bockaert J, Marin P (2006) The proteomic analysis of mouse choroid plexus secretome reveals a high protein secretion capacity of choroidal epithelial cells. Proteomics 6:5941–5952

    Article  CAS  Google Scholar 

  21. Gard AL, Gavin E, Solodushko V, Pennica D (2004) Cardiotrophin-1 in choroid plexus and the cerebrospinal fluid circulatory system. Neuroscience 127(1):43–52

    Article  CAS  Google Scholar 

  22. Thanos CG, Schneider PA, Bintz BE, Jensen R, Bryant B, Bell WJ, Hudak J, Emerich DF (2007) The in vitro expression and secretion of vascular endothelial growth factor from free and alginate-polyornithine encapsulated choroid plexus epithelium. Tissue Eng 13(4):747–756

    Article  CAS  Google Scholar 

  23. Ericsson A, Liu C, Hart RP, Sawchenko PE (1995) Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol 361(4):681–698

    Article  CAS  Google Scholar 

  24. Nadeau S, Rivest S (1999) Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 93(4):1449–1464

    Article  CAS  Google Scholar 

  25. Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea JF, Chodobski A (2009) The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab 29(9):1503–1516

    Article  CAS  Google Scholar 

  26. Thanos CG, Bintz BE, Emerich DF (2009) Microencapsulated choroid plexus epithelial cell transplants for repair of the brain, vol 670, Advances in experimental medicine and biology: therapeutic applications of cell microencapsulation. Landes Bioscience, Austin, TX

    Google Scholar 

  27. Aliaghaei A, Digaleh H, Khodagholi F, Ahmadiani A (2015) Encapsulated choroid plexus epithelial cells actively protect against intrahippocampal abeta-induced long-term memory dysfunction; upregulation of effective neurogenesis with the abrogated apoptosis and neuroinflammation. J Mol Neurosci 56(3):708–721. doi:10.1007/s12031-015-0492-y

    Article  CAS  Google Scholar 

  28. Lim F, Sun AM (1981) Microencapsulated islets in diabetic rats. Science 213(4512):1146. doi:10.1126/science.213.4512.1146-a

    Article  CAS  Google Scholar 

  29. Omer A, Duvivier-Kali V, Fernandes J, Tchipashvili V, Colton CK, Weir GC (2005) Long-term normoglycemia in rats receiving transplants with encapsulated islets. Transplantation 79(1):52–58

    Article  CAS  Google Scholar 

  30. Khanna O, Larson JC, Moya ML, Opara EC, Brey EM (2012) Generation of alginate microspheres for biomedical applications. J Vis Exp (66). doi: 10.3791/3388

    Google Scholar 

  31. Pareta R, McQuilling JP, Sittadjody S, Jenkins R, Bowden S, Orlando G, Farney AC, Brey EM, Opara EC (2014) Long-term function of islets encapsulated in a redesigned alginate microcapsule construct in omentum pouches of immune-competent diabetic rats. Pancreas 43(4):605–613. doi:10.1097/MPA.0000000000000107

    Article  CAS  Google Scholar 

  32. Moya ML, Cheng MH, Huang JJ, Francis-Sedlak ME, Kao SW, Opara EC, Brey EM (2010) The effect of FGF-1 loaded alginate microbeads on neovascularization and adipogenesis in a vascular pedicle model of adipose tissue engineering. Biomaterials 31(10):2816–2826. doi:10.1016/j.biomaterials.2009.12.053

    Article  CAS  Google Scholar 

  33. Fjord-Larsen L, Kusk P, Emerich DF, Thanos C, Torp M, Bintz B, Tornoe J, Johnsen AH, Wahlberg LU (2012) Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene Ther 19(10):1010–1017. doi:10.1038/gt.2011.178

    Article  CAS  Google Scholar 

  34. Skinner SJ, Geaney MS, Rush R, Rogers ML, Emerich DF, Thanos CG, Vasconcellos AV, Tan PL, Elliott RB (2006) Choroid plexus transplants in the treatment of brain diseases. Xenotransplantation 13(4):284–288. doi:10.1111/j.1399-3089.2006.00310.x

    Article  Google Scholar 

  35. Emerich DF, Thanos CG (2006) In vitro culture duration does not impact the ability of encapsulated choroid plexus transplants to prevent neurological deficits in an excitotoxin-lesioned rat model of Huntington’s disease. Cell Transplant 15(7):595–602

    Article  Google Scholar 

  36. Thanos CG, Bintz B, Emerich DF (2010) Microencapsulated choroid plexus epithelial cell transplants for repair of the brain. Adv Exp Med Biol 670:80–91

    Article  CAS  Google Scholar 

  37. Borlongan CV, Thanos CG, Skinner SJ, Geaney M, Emerich DF (2008) Transplants of encapsulated rat choroid plexus cells exert neuroprotection in a rodent model of Huntington’s disease. Cell Transplant 16(10):987–992

    Article  Google Scholar 

  38. Luo XM, Lin H, Wang W, Geaney MS, Law L, Wynyard S, Shaikh SB, Waldvogel H, Faull RL, Elliott RB, Skinner SJ, Lee JE, Tan PL (2013) Recovery of neurological functions in non-human primate model of Parkinson’s disease by transplantation of encapsulated neonatal porcine choroid plexus cells. J Parkinsons Dis 3(3):275–291. doi:10.3233/JPD-130214

    CAS  Google Scholar 

  39. Skinner SJ, Lin H, Geaney MS, Gorba T, Elliott RB, Tan PL (2011) Restoration of motor control and dopaminergic activity in rats with unilateral 6-hydroxy-dopamine lesions. Regen Med 6(3):319–326. doi:10.2217/rme.11.15

    Article  CAS  Google Scholar 

  40. Thanos CG, Elliott RB (2009) Encapsulated porcine islet transplantation: an evolving therapy for the treatment of type I diabetes. Expert Opin Biol Ther 9(1):29–44

    Article  CAS  Google Scholar 

  41. Sharma HS, Tang ZH, Gho BC, Verdouw PD (1995) Nucleotide sequence and expression of the porcine vascular endothelial growth factor. Biochim Biophys Acta 1260(2):235–238

    Article  Google Scholar 

  42. Li SH, Cheng AL, Li H, Li XJ (1999) Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J Neurosci 19(13):5159–5172

    CAS  Google Scholar 

  43. Emerich DF, Winn SR, Hantraye PM, Peschanski M, Chen EY, Chu Y, McDermott P, Baetge EE, Kordower JH (1997) Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386(6623):395–399. doi:10.1038/386395a0

    Article  CAS  Google Scholar 

  44. Wolf HK, Buslei R, Schmidt-Kastner R, Schmidt-Kastner PK, Pietsch T, Wiestler OD, Blumcke I (1996) NeuN: a useful neuronal marker for diagnostic histopathology. J Histochem Cytochem 44(10):1167–1171

    Article  CAS  Google Scholar 

  45. West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231(4):482–497. doi:10.1002/ar.1092310411

    Article  CAS  Google Scholar 

  46. Kordower JH, Chu Y, Stebbins GT, DeKosky ST, Cochran EJ, Bennett D, Mufson EJ (2001) Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 49(2):202–213

    Article  CAS  Google Scholar 

  47. Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH (2002) Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 450(3):203–214. doi:10.1002/cne.10261

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Cytosolv, Inc., 117 Chapman Street, Suite 107, Providence, RI, 02905, USA

    M. A. Sandrof & Chris G. Thanos Ph.D.

  2. NS Gene, Providence, RI, USA

    D. F. Emerich

Authors
  1. M. A. Sandrof
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  2. D. F. Emerich
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  3. Chris G. Thanos Ph.D.
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Corresponding author

Correspondence to Chris G. Thanos Ph.D. .

Editor information

Editors and Affiliations

  1. Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

    Emmanuel C. Opara

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Sandrof, M.A., Emerich, D.F., Thanos, C.G. (2017). Primary Choroid Plexus Tissue for Use in Cellular Therapy. In: Opara, E. (eds) Cell Microencapsulation. Methods in Molecular Biology, vol 1479. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6364-5_19

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  • DOI: https://doi.org/10.1007/978-1-4939-6364-5_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6362-1

  • Online ISBN: 978-1-4939-6364-5

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