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01-12-2020 | Radiotherapy | Research

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1⁺ stem cells from young donors

Authors: Lukasz Wlodarek, Feng Cao, Faisal J. Alibhai, Adam Fekete, Nima Noyan, Stephanie W. Tobin, Tina B. Marvasti, Jun Wu, Shu-Hong Li, Richard D. Weisel, Lu-Yang Wang, Zhengping Jia, Ren-Ke Li

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Background

Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.

Methods

Here we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.

Results

Regardless of donor age, GFP⁺ cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP⁺/Iba1⁺ cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively.

Conclusion

Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.

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de Robles P, et al. The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis. Neuro-Oncology. 2016;17(6):776–83.CrossRef

Gondi V, Hermann BP, Mehta MP, Tomé WA. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys. 2013;85(2):348–54.PubMedCrossRef

Brown PD, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1049–60.PubMedPubMedCentralCrossRef

Gomez-Millan J. Radiation therapy in the elderly: more side effects and complications? Crit Rev Oncol Hematol. 2009;71(1):70–8.PubMedCrossRef

Buga AM, Vintilescu R, Pop OT, Popa-Wagner A. Brain aging and regeneration after injuries: an organismal approach. Aging Dis. 2011;2(1):64–79.PubMedPubMedCentral

Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell. 2014;13(1):60–9.PubMedCrossRef

Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412–24.PubMedCrossRef

Koellhoffer EC, McCullough LD, Ritzel RM. Old maids: aging and its impact on microglia function. Int J Mol Sci. 2017;18(4):769.PubMedCentralCrossRef

Orre M, et al. Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging. 2014;35(1):1–14.PubMedCrossRef

10.

Harry GJ. Microglia during development and aging. Pharmacol Ther. 2013;139(3):313–26.PubMedPubMedCentralCrossRef

11.

Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45. https://doi.org/10.3389/fncel.2013.00045.CrossRefPubMedPubMedCentral

12.

Ginhoux F, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.PubMedPubMedCentralCrossRef

13.

Hashimoto D, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792–804.PubMedCrossRef

14.

Elmore MR, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82(2):380–97.PubMedPubMedCentralCrossRef

15.

Bruttger J, et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity. 2015;43(1):92–106.PubMedCrossRef

16.

Askew K, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 2017;18(2):391–405.PubMedPubMedCentralCrossRef

17.

Huang Y, et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci. 2018;21(4):530–40.PubMedCrossRef

18.

Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A. 1997;94(8):4080–5.PubMedPubMedCentralCrossRef

19.

Djukic M, et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain. 2006;129(Pt 9):2394–403.PubMedCrossRef

20.

Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006;49(4):489–502.PubMedCrossRef

21.

Cronk JC, et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J Exp Med. 2018;215(6):1627–47.PubMedPubMedCentralCrossRef

22.

Lund H, et al. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat Commun. 2018;9(1):4845.PubMedPubMedCentralCrossRef

23.

Biju KC, et al. Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson's disease. Neurosci Lett. 2013;535:24–9.PubMedPubMedCentralCrossRef

24.

Sasahara M, et al. Activation of bone marrow-derived microglia promotes photoreceptor survival in inherited retinal degeneration. Am J Pathol. 2008;172(6):1693–703.PubMedPubMedCentralCrossRef

25.

Ritzel RM, et al. Aging alters the immunological response to ischemic stroke. Acta Neuropathol. 2018;136(1):89–110.PubMedPubMedCentralCrossRef

26.

Pérez-Escudero A, Vicente-Page J, Hinz RC, Arganda S, de Polavieja GG. idTracker: tracking individuals in a group by automatic identification of unmarked animals. Nat Methods. 2014;11(7):743–8.PubMedCrossRef

27.

Leger M, et al. Object recognition test in mice. Nat Protoc. 2013;8(12):2531–7.PubMedCrossRef

28.

Sunyer B, Patil S, Höger H, Lubec G. Barnes maze, a useful task to assess spatial reference memory in the mice. Protoc Exch. 2007. https://doi.org/10.1038/nprot.2007.390.

29.

Risher WC, Ustunkaya T, Singh Alvarado J, Eroglu C. Rapid Golgi analysis method for efficient and unbiased classification of dendritic spines. PLoS One. 2014;9(9):e107591.PubMedPubMedCentralCrossRef

30.

Haus DL, et al. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury. Exp Neurol. 2016;281:1–16.PubMedCrossRef

31.

Parkhurst CN, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;55(7):1596–609.CrossRef

32.

Paolicelli RC, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456–8.PubMedCrossRef

33.

Ribeiro Xavier AL, Kress BT, Goldman SA, Lacerda de Menezes JR, Nedergaard M. A distinct population of microglia supports adult neurogenesis in the subventricular zone. J Neurosci. 2015;35(34):11848–61.PubMedPubMedCentralCrossRef

34.

Hickman SE, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–905.PubMedPubMedCentralCrossRef

35.

Flowers A, Bell-Temin H, Jalloh A, Stevens SM Jr, Bickford PC. Proteomic analysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response. J Neuroinflammation. 2017;14(1):96. https://doi.org/10.1186/s12974-017-0840-7.CrossRefPubMedPubMedCentral

36.

Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging. 2006;27(5):717–22.PubMedCrossRef

37.

Godbout JP, et al. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 2005;19(10):1329–31.PubMedCrossRef

38.

Armstrong GT, et al. Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy. J Natl Cancer Inst. 2013;105(12):899–907.PubMedPubMedCentralCrossRef

39.

Greene-Schloesser D, Robbins ME. Radiation-induced cognitive impairment--from bench to bedside. Neuro-Oncology. 2012;14(Suppl 4):iv37–44.PubMedPubMedCentralCrossRef

40.

Lever C, Burton S, O'Keefe J. Rearing on hind legs, environmental novelty, and the hippocampal formation. Rev Neurosci. 2006;17(1–2):111–33.PubMed

41.

Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A. 2016;113(51):14835–40.PubMedPubMedCentralCrossRef

42.

Burney S, Caulfield JL, Niles JC, Wishnok JS, Tannenbaum SR. The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res. 1999;424(1–2):37–49.PubMedCrossRef

43.

Dye NB, Gondi V, Mehta MP. Strategies for preservation of memory function in patients with brain metastases. Chin Clin Oncol. 2015;4(2). https://doi.org/10.3978/j.issn.2304-3865.2015.05.05.

44.

Tang J, et al. Embryonic stem cell-derived neural precursor cells improve memory dysfunction in Abeta (1-40) injured rats. Neurosci Res. 2008;62(2):86–96.PubMedCrossRef

45.

Blurton-Jones M, et al. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009;106(32):13594–9.PubMedPubMedCentralCrossRef

46.

Villeda SA, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659–63.PubMedPubMedCentralCrossRef

47.

Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10(12):1538–43.PubMedCrossRef

48.

Wang HB, et al. Reduced ischemic injury after stroke in mice by angiogenic gene delivery via ultrasound-targeted microbubble destruction. J Neuropathol Exp Neurol. 2014;73(6):548–58.PubMedCrossRef

49.

Kierdorf K, Katzmarski N, Haas CA, Prinz M. Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One. 2013;8(3):e58544.PubMedPubMedCentralCrossRef

50.

Asheuer M, et al. Human CD34+ cells differentiate into microglia and express recombinant therapeutic protein. Proc Natl Acad Sci U S A. 2004;101(10):3557–62.PubMedPubMedCentralCrossRef

51.

Dietrich J, et al. Bone marrow drives central nervous system regeneration after radiation injury. J Clin Invest. 2018;128(1):281–93.PubMedCrossRef

52.

Moravan MJ, Olschowka JA, Williams JP, O'Banion MK. Brain radiation injury leads to a dose- and time-dependent recruitment of peripheral myeloid cells that depends on CCR2 signaling. J Neuroinflammation. 2016;13:30. https://doi.org/10.1186/s12974-016-0496-8.CrossRefPubMedPubMedCentral

53.

Hordeaux J, et al. The GPI-linked protein LY6A drives AAV-PHP.B transport across the blood-brain barrier. Mol Ther. 2019;27(5):912–21.PubMedCrossRefPubMedCentral

54.

Chen HHW, Kuo MT. Improving radiotherapy in cancer treatment: promises and challenges. Oncotarget. 2017;8(37):62742–58.PubMedPubMedCentral

55.

Mitin T, Zietman AL. Promise and pitfalls of heavy-particle therapy. J Clin Oncol. 2014;32(26):2855–63.PubMedPubMedCentralCrossRef

56.

Newhauser WD, Berrington de Gonzalez A, Schulte R, Lee C. A review of radiotherapy-induced late effects research after advanced technology treatments. Front Oncol. 2016;6:13.PubMedPubMedCentralCrossRef

57.

Rola R, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol. 2004;188(2):316–30.PubMedCrossRef

58.

Gibson BW, et al. Comparison of cesium-137 and X-ray irradiators by using bone marrow transplant reconstitution in C57BL/6J mice. Comp Med. 2015;65(3):165–72.PubMedPubMedCentral

59.

Paix A, et al. Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: a review. Crit Rev Oncol Hematol. 2018;123:138–48.PubMedCrossRef

60.

Arnold KM, et al. The impact of radiation on the tumor microenvironment: effect of dose and fractionation schedules. Cancer Growth Metastasis. 2018;11:1179064418761639.PubMedPubMedCentralCrossRef

61.

Steen RG, Spence D, Wu S, Xiong X, Kun LE, Merchant TE. Effect of therapeutic ionizing radiation on the human brain. Ann Neurol. 2001;50(6):787–95.PubMedCrossRef

62.

Cosset JM, Girinsky T, Malaise E, Chaillet MP, Dutreix J. Clinical basis for TBI fractionation. Radiother Oncol. 1990;18(Suppl 1):60–7.PubMedCrossRef

63.

Harder H, Cornelissen JJ, Van Gool AR, Duivenvoorden HJ, Eijkenboom WM, van den Bent MJ. Cognitive functioning and quality of life in long-term adult survivors of bone marrow transplantation. Cancer. 2002;95(1):183–92.PubMedCrossRef

64.

Harder H, Duivenvoorden HJ, van Gool AR, Cornelissen JJ, van den Bent MJ. Neurocognitive functions and quality of life in haematological patients receiving haematopoietic stem cell grafts: a one-year follow-up pilot study. J Clin Exp Neuropsychol. 2006;28(3):283–93.PubMedCrossRef

65.

Sostak P, Padovan CS, Yousry TA, Ledderose G, Kolb HJ, Straube A. Prospective evaluation of neurological complications after allogeneic bone marrow transplantation. Neurology. 2003;60(5):842–8.PubMedCrossRef

66.

Soule BP, et al. Pulmonary function following total body irradiation (with or without lung shielding) and allogeneic peripheral blood stem cell transplant. Bone Marrow Transplant. 2007;40(6):573–8.PubMedCrossRef

67.

O'Donovan A, Leech M, Gillham C. Assessment and management of radiotherapy induced toxicity in older patients. J Geriatr Oncol. 2017;8(6):421–7.PubMedCrossRef

68.

Sousa-Victor P, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014;506(7488):316–21.PubMedCrossRef

69.

Goodus MT, Guzman AM, Calderon F, Jiang Y, Levison SW. Neural stem cells in the immature, but not the mature, subventricular zone respond robustly to traumatic brain injury. Dev Neurosci. 2015;37(1):29–42.PubMedCrossRef

70.

Tierney MT, Stec MJ, Rulands S, Simons BD, Sacco A. Muscle stem cells exhibit distinct clonal dynamics in response to tissue repair and homeostatic aging. Cell Stem Cell. 2015;22(1):119–27.CrossRef

71.

Ge R, et al. Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke. J Neuroinflammation. 2017;14(1):153. https://doi.org/10.1186/s12974-017-0909-3.CrossRefPubMedPubMedCentral

72.

Hasegawa-Ishii S, et al. Increased recruitment of bone marrow-derived cells into the brain associated with altered brain cytokine profile in senescence-accelerated mice. Brain Struct Funct. 2016;221(3):1513–31.PubMedCrossRef

73.

Arnhold S, et al. Human bone marrow stroma cells display certain neural characteristics and integrate in the subventricular compartment after injection into the liquor system. Eur J Cell Biol. 2006;85(6):551–65.PubMedCrossRef

74.

Das MM, et al. Young bone marrow transplantation preserves learning and memory in old mice. Commun Biol. 2019;2:73. https://doi.org/10.1038/s42003-019-0298-5.CrossRefPubMedPubMedCentral

75.

Yang J, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci U S A. 2013;110(37):15049–54.PubMedPubMedCentralCrossRef

76.

Jenrow KA, Brown SL, Lapanowski K, Naei H, Kolozsvary A, Kim JH. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res. 2013;179(5):549–56.PubMedPubMedCentralCrossRef

77.

Yang KQ, et al. Bone marrow-derived mesenchymal stem cells induced by inflammatory cytokines produce angiogenetic factors and promote prostate cancer growth. BMC Cancer. 2017;17(1):878.PubMedPubMedCentralCrossRef

78.

Mi F, Gong L. Secretion of interleukin-6 by bone marrow mesenchymal stem cells promotes metastasis in hepatocellular carcinoma. Biosci Rep. 2017;37(4):BSR20170181.PubMedPubMedCentralCrossRef

79.

Efremov YM, Dokrunova AA, Efremenko AV, Kirpichnikov MP, Shaitan KV, Sokolova OS. Distinct impact of targeted actin cytoskeleton reorganization on mechanical properties of normal and malignant cells. Biochim Biophys Acta. 2015;1853(11 Pt B):3117–25.PubMedCrossRef

80.

Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773(5):642–52.PubMedCrossRef

81.

White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Henley SJ. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med. 2014;46(3 Suppl 1):S7–15.PubMedPubMedCentralCrossRef

82.

Yoneda T, Hiraga T. Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun. 2005;328(3):679–87.PubMedCrossRef

83.

Lawrence YR, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S20–7.PubMedPubMedCentralCrossRef

Title: Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors
Authors: Lukasz Wlodarek
Feng Cao
Faisal J. Alibhai
Adam Fekete
Nima Noyan
Stephanie W. Tobin
Tina B. Marvasti
Jun Wu
Shu-Hong Li
Richard D. Weisel
Lu-Yang Wang
Zhengping Jia
Ren-Ke Li
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Radiotherapy
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-019-1681-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1⁺ stem cells from young donors

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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