, Volume 21, Issue 4, pp 667–675 | Cite as

Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome

  • Daniel A. P. Guerra
  • Ana E. Paiva
  • Isadora F. G. Sena
  • Patrick O. Azevedo
  • Walison N. Silva
  • Akiva Mintz
  • Alexander BirbrairEmail author
Review Paper


Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood–brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood–brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte’s role in the glioblastoma microenvironment.


Pericytes Glioblastoma Blood–brain barrier Chemotherapy 



Alexander Birbrair is supported by a grant from Instituto Serrapilheira/Serra-1708-15285, a Grant from Pró-reitoria de Pesquisa/Universidade Federal de Minas Gerais (PRPq/UFMG) (Edital 05/2016); a Grant from FAPEMIG [Rede Mineira de Engenharia de Tecidos e Terapia Celular (REMETTEC, RED-00570-16)], and a Grant from FAPEMIG [Rede De Pesquisa Em Doenças Infecciosas Humanas E Animais Do Estado De Minas Gerais (RED-00313-16)]; Akiva Mintz is supported by the National Institute of Health (1R01CA179072-01A1) and by the American Cancer Society Mentored Research Scholar Grant (124443-MRSG-13-121-01-CDD).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123. CrossRefPubMedGoogle Scholar
  2. 2.
    Fisher PG, Buffler PA (2005) Malignant gliomas in 2005: where to GO from here? JAMA 293(5):615–617. CrossRefPubMedGoogle Scholar
  3. 3.
    Reardon DA, Rich JN, Friedman HS, Bigner DD (2006) Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 24(8):1253–1265. CrossRefPubMedGoogle Scholar
  4. 4.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. CrossRefGoogle Scholar
  5. 5.
    Kortmann RD, Jeremic B, Weller M, Plasswilm L, Bamberg M (2003) Radiochemotherapy of malignant glioma in adults. Strahlentherapie und Onkologie 179(4):219–232. CrossRefPubMedGoogle Scholar
  6. 6.
    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-Oncology. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain Radiation Oncology T G, National Cancer Institute of Canada Clinical Trials G (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466. CrossRefGoogle Scholar
  8. 8.
    Inskip PD, Linet MS, Heineman EF (1995) Etiology of brain tumors in adults. Epidemiol Rev 17(2):382–414CrossRefGoogle Scholar
  9. 9.
    Woernle CM, Peus D, Hofer S, Rushing EJ, Held U, Bozinov O, Krayenbuhl N, Weller M, Regli L (2015) Efficacy of surgery and further treatment of progressive glioblastoma. World Neurosurg 84(2):301–307. CrossRefPubMedGoogle Scholar
  10. 10.
    Birbrair A, Sattiraju A, Zhu D, Zulato G, Batista I, Nguyen VT, Messi ML, Solingapuram Sai KK, Marini FC, Delbono O, Mintz A (2017) Novel peripherally derived neural-like stem cells as therapeutic carriers for treating glioblastomas. Stem Cells Transl Med 6(2):471–481. CrossRefPubMedGoogle Scholar
  11. 11.
    Darefsky AS, King JT Jr, Dubrow R (2012) Adult glioblastoma multiforme survival in the temozolomide era: a population-based analysis of Surveillance, Epidemiology, and End Results registries. Cancer 118(8):2163–2172. CrossRefPubMedGoogle Scholar
  12. 12.
    Azevedo PO, Lousado L, Paiva AE, Andreotti JP, Santos GSP, Sena IFG, Prazeres PHDM, Filev R, Mintz A, Birbrair A (2017) Endothelial cells maintain neural stem cells quiescent in their niche. Neurosci 363:62–65CrossRefGoogle Scholar
  13. 13.
    Coatti GC, Frangini M, Valadares MC, Gomes JP, Lima NO, Cavaçana N, Assoni AF, Pelatti MV, Birbrair A, de Lima ACP, Singer JM, Rocha RMM, Da Silva GL, Mantovani MS, Macedo-Souza LI, Ferrari MFR, Zatz M (2017) Pericytes Extend Survival of ALS SOD1 Mice and Induce the Expression of Antioxidant Enzymes in the Murine Model and in IPSCs Derived Neuronal Cells from an ALS Patient. Stem Cell Rev Rep 13(5):686–698CrossRefGoogle Scholar
  14. 14.
    Prazeres PHDM, Almeida VM, Lousado L, Andreotti JP, Paiva AE, Santos GSP, Azevedo PO, Souto L, Almeida GG, Filev R, Mintz A, Gonçalves R, Birbrair A (2018) Macrophages Generate Pericytes in the Developing Brain. Cell Mol Neurobiol 38(4):777–782CrossRefGoogle Scholar
  15. 15.
    Santos GSP, Prazeres P, Mintz A, Birbrair A (2017) Role of pericytes in the retina. Eye. CrossRefPubMedGoogle Scholar
  16. 16.
    Theodorakis PE, Muller EA, Craster RV, Matar OK (2017) Physical insights into the blood-brain barrier translocation mechanisms. Phys Biol 14(4):041001. CrossRefPubMedGoogle Scholar
  17. 17.
    Parrish KE, Sarkaria JN, Elmquist WF (2015) Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clin Pharmacol Ther 97(4):336–346. CrossRefPubMedGoogle Scholar
  18. 18.
    Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34(1):207–217CrossRefGoogle Scholar
  19. 19.
    Karim R, Palazzo C, Evrard B, Piel G (2016) Nanocarriers for the treatment of glioblastoma multiforme: current state-of-the-art. J Control Release 227:23–37. CrossRefGoogle Scholar
  20. 20.
    Oberoi RK, Parrish KE, Sio TT, Mittapalli RK, Elmquist WF, Sarkaria JN (2016) Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro-Oncology 18(1):27–36. CrossRefPubMedGoogle Scholar
  21. 21.
    Pardridge WM (2012) Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 32(11):1959–1972. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Paiva AE, Lousado L, Almeida VM, Andreotti JP, Santos GSP, Azevedo PO, Sena IFG, Prazeres PHDM, Borges IT, Azevedo V, Mintz A, Birbrair A (2017) Endothelial Cells as Precursors for Osteoblasts in the Metastatic Prostate Cancer Bone. Neoplasia 19(11):928–931CrossRefGoogle Scholar
  23. 23.
    Prazeres PHDM, Turquetti Anaelise OM, Azevedo PO, Barreto RSN, Miglino MA, Mintz A, Delbono O, Birbrair A (2018) Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis. Int J Biochem Cell Biol 99:109–113CrossRefGoogle Scholar
  24. 24.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Enikolopov GN, Mintz A, Delbono O (2013) Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res 10(1):67–84. CrossRefPubMedGoogle Scholar
  25. 25.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (2015) Pericytes at the intersection between tissue regeneration and pathology. Clin Sci 128(2):81–93. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Costa MA, Paiva AE, Andreotti JP, Cardoso MV, Cardoso CD, Mintz A, Birbrair A (2018) Pericytes constrict blood vessels after myocardial ischemia. J Mol Cell Cardiol. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Almeida VM, Paiva AE, Sena IFG, Mintz A, Magno LAV, Birbrair A (2017) Pericytes make spinal cord breathless after injury. Neuroscientist. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68(3):409–427. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, Huang Z, Zhai K, Ke SQ, Ping YF, Feng H, Rich JN, Yu JS, Bao S, Bian XW (2017) Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem C21(5):591–603. CrossRefGoogle Scholar
  30. 30.
    Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153(1):139–152. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84(10):1424–1431. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Gotthardt D, Putz EM, Grundschober E, Prchal-Murphy M, Straka E, Kudweis P, Heller G, Bago-Horvath Z, Witalisz-Siepracka A, Cumaraswamy AA, Gunning PT, Strobl B, Muller M, Moriggl R, Stockmann C, Sexl V (2016) STAT5 is a key regulator in NK cells and acts as a molecular switch from tumor surveillance to tumor promotion. Cancer Discov 6(4):414–429. CrossRefPubMedGoogle Scholar
  33. 33.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Azevedo PO, Paiva AE, Santos GSP, Lousado L, Andreotti JP, Sena IFG, Mintz A, Birbrair A (2018) Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression. Cancer Metastasis Rev (in press)Google Scholar
  35. 35.
    Azevedo PO, Sena IFG, Andreotti JP, Carvalho-Tavares J, Alves-Filho JC, Cunha TM, Cunha FQ, Mintz A, Birbrair A (2018) Pericytes modulate myelination in the central nervous system. J Cell Physiol 233(8):5523–5529CrossRefGoogle Scholar
  36. 36.
    Guijarro-Munoz I, Compte M, Alvarez-Cienfuegos A, Alvarez-Vallina L, Sanz L (2014) Lipopolysaccharide activates toll-like receptor 4 (TLR4)-mediated NF-kappaB signaling pathway and proinflammatory response in human pericytes. J Biol Chem 289(4):2457–2468. CrossRefPubMedGoogle Scholar
  37. 37.
    Andreotti JP, Paiva AE, Prazeres P, Guerra DAP, Silva WN, Vaz RS, Mintz A, Birbrair A (2018) The role of natural killer cells in the uterine microenvironment during pregnancy. Cell Mol Immunol. CrossRefPubMedGoogle Scholar
  38. 38.
    Asada N, Kunisaki Y, Pierce H, Wang Z, Fernandez NF, Birbrair A, Ma’ayan A, Frenette PS (2017) Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol 19(3):214–223. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sena IFG, Paiva AE, Prazeres PHDM, Azevedo PO, Lousado L, Bhutia SK, Salmina AB, Mintz A, Birbrair A (2018) Glioblastoma-activated pericytes support tumor growth via immunosuppression. Cancer Med. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Balabanov R, Beaumont T, Dore-Duffy P (1999) Role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J Neurosci Res 55(5):578–587CrossRefGoogle Scholar
  41. 41.
    Tu Z, Li Y, Smith DS, Sheibani N, Huang S, Kern T, Lin F (2011) Retinal pericytes inhibit activated T cell proliferation. Investig Ophthalmol Vis Sci 52(12):9005–9010. CrossRefGoogle Scholar
  42. 42.
    Verbeek MM, Westphal JR, Ruiter DJ, de Waal RM (1995) T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions. J Immunol 154(11):5876–5884PubMedGoogle Scholar
  43. 43.
    Fabry Z, Fitzsimmons KM, Herlein JA, Moninger TO, Dobbs MB, Hart MN (1993) Production of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes. J Neuroimmunol 47(1):23–34CrossRefGoogle Scholar
  44. 44.
    Stark K, Eckart A, Haidari S, Tirniceriu A, Lorenz M, von Bruhl ML, Gartner F, Khandoga AG, Legate KR, Pless R, Hepper I, Lauber K, Walzog B, Massberg S (2013) Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat Immunol 14(1):41–51. CrossRefPubMedGoogle Scholar
  45. 45.
    Kim JA, Tran ND, Li Z, Yang F, Zhou W, Fisher MJ (2006) Brain endothelial hemostasis regulation by pericytes. J Cereb Blood Flow Metab 26(2):209–217. CrossRefPubMedGoogle Scholar
  46. 46.
    Fisher M (2009) Pericyte signaling in the neurovascular unit. Stroke 40(3 Suppl):S13–S15. CrossRefGoogle Scholar
  47. 47.
    Bouchard BA, Shatos MA, Tracy PB (1997) Human brain pericytes differentially regulate expression of procoagulant enzyme complexes comprising the extrinsic pathway of blood coagulation. Arterioscler Thromb Vasc Biol 17(1):1–9CrossRefGoogle Scholar
  48. 48.
    Jeynes B (1985) Reactions of granular pericytes in a rabbit cerebrovascular ischemia model. Stroke 16(1):121–125CrossRefGoogle Scholar
  49. 49.
    Balabanov R, Washington R, Wagnerova J, Dore-Duffy P (1996) CNS microvascular pericytes express macrophage-like function, cell surface integrin alpha M, and macrophage marker ED-2. Microvasc Res 52(2):127–142. CrossRefPubMedGoogle Scholar
  50. 50.
    Thomas WE (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Rev 31(1):42–57CrossRefGoogle Scholar
  51. 51.
    Hasan M, Glees P (1990) The fine structure of human cerebral perivascular pericytes and juxtavascular phagocytes: their possible role in hydrocephalic edema resolution. J Hirnforsch 31(2):237–249PubMedGoogle Scholar
  52. 52.
    Castejon OJ (2011) Ultrastructural pathology of cortical capillary pericytes in human traumatic brain oedema. Folia Neuropathol 49(3):162–173PubMedGoogle Scholar
  53. 53.
    Valdor R, Garcia-Bernal D, Bueno C, Rodenas M, Moraleda JM, Macian F, Martinez S (2017) Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells. Oncotarget 8(40):68614–68626. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sena IFG, Paiva AE, Prazeres P, Azevedo PO, Lousado L, Bhutia SK, Salmina AB, Mintz A, Birbrair A (2018) Glioblastoma-activated pericytes support tumor growth via immunosuppression. Cancer Med. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38. CrossRefGoogle Scholar
  56. 56.
    Keskin D, Kim J, Cooke VG, Wu CC, Sugimoto H, Gu C, De Palma M, Kalluri R, LeBleu VS (2015) Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep 10(7):1066–1081. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Hainsworth JD, Spigel DR, Sosman JA, Burris HA 3rd, Farley C, Cucullu H, Yost K, Hart LL, Sylvester L, Waterhouse DM, Greco FA (2007) Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial. Clin Genitourin Cancer 5(7):427–432. CrossRefPubMedGoogle Scholar
  58. 58.
    Nisancioglu MH, Betsholtz C, Genove G (2010) The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. Cancer Res 70(12):5109–5115. CrossRefPubMedGoogle Scholar
  59. 59.
    Mezheyeuski A, Bradic Lindh M, Guren TK, Dragomir A, Pfeiffer P, Kure EH, Ikdahl T, Skovlund E, Corvigno S, Strell C, Pietras K, Ponten F, Mulder J, Qvortrup C, Portyanko A, Tveit KM, Glimelius B, Sorbye H, Ostman A (2016) Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer. Oncotarget 7(27):41948–41958. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Investig 116(3):642–651. CrossRefPubMedGoogle Scholar
  61. 61.
    Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M (2005) Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 69(2):159–166. CrossRefPubMedGoogle Scholar
  62. 62.
    Hong J, Tobin NP, Rundqvist H, Li T, Lavergne M, Garcia-Ibanez Y, Qin H, Paulsson J, Zeitelhofer M, Adzemovic MZ, Nilsson I, Roswall P, Hartman J, Johnson RS, Ostman A, Bergh J, Poljakovic M, Genove G (2015) Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J Natl Cancer Inst. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer cell 21(1):66–81. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Birbrair A, Borges IDT, Gilson Sena IF, Almeida GG, da Silva Meirelles L, Goncalves R, Mintz A, Delbono O (2017) How plastic are pericytes? Stem cells development 26(14):1013–1019. CrossRefPubMedGoogle Scholar
  65. 65.
    Khan JA, Mendelson A, Kunisaki Y, Birbrair A, Kou Y, Arnal-Estape A, Pinho S, Ciero P, Nakahara F, Ma’ayan A, Bergman A, Merad M, Frenette PS (2016) Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 351(6269):176–180. CrossRefPubMedGoogle Scholar
  66. 66.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (2013) Type-1 pericytes participate in fibrous tissue deposition in aged skeletal muscle. Am J Physiol Cell Physiol 305(11):C1098–C1113. CrossRefGoogle Scholar
  67. 67.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Enikolopov GN, Mintz A, Delbono O (2013) Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells Dev 22(16):2298–2314. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang ZM, Messi ML, Mintz A, Delbono O (2014) Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Res Ther 5(6):122. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Dore-Duffy P, Katychev A, Wang X, Van Buren E (2006) CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 26(5):613–624. CrossRefPubMedGoogle Scholar
  70. 70.
    Paul G, Ozen I, Christophersen NS, Reinbothe T, Bengzon J, Visse E, Jansson K, Dannaeus K, Henriques-Oliveira C, Roybon L, Anisimov SV, Renstrom E, Svensson M, Haegerstrand A, Brundin P (2012) The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS ONE 7(4):e35577. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Karow M, Sanchez R, Schichor C, Masserdotti G, Ortega F, Heinrich C, Gascon S, Khan MA, Lie DC, Dellavalle A, Cossu G, Goldbrunner R, Gotz M, Berninger B (2012) Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 11(4):471–476. CrossRefPubMedGoogle Scholar
  72. 72.
    Nakagomi T, Kubo S, Nakano-Doi A, Sakuma R, Lu S, Narita A, Kawahara M, Taguchi A, Matsuyama T (2015) Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. Stem Cells 33(6):1962–1974. CrossRefPubMedGoogle Scholar
  73. 73.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Enikolopov GN, Mintz A, Delbono O (2013) Skeletal muscle neural progenitor cells exhibit properties of NG2-glia. Exp Cell Res 319(1):45–63. CrossRefPubMedGoogle Scholar
  74. 74.
    Birbrair A, Delbono O (2015) Pericytes are Essential for Skeletal Muscle Formation. Stem Cell Rev Rep 11(4):547–548CrossRefGoogle Scholar
  75. 75.
    Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (2014) Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Front Aging Neurosci. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Pereira LX, Viana CTR, Orellano LAA, Almeida SA, Vasconcelos AC, de Miranda Goes A, Birbrair A, Andrade SP, Campos PP (2017) Synthetic matrix of polyether-polyurethane as a biological platform for pancreatic regeneration. Life Sci 176:67–74CrossRefGoogle Scholar
  77. 77.
    Paiva AE, Lousado L, Guerra DAP, Azevedo PO, Sena IFG, Andreotti JP, Santos GSP, Goncalves R, Mintz A, Birbrair A (2018) Pericytes in the premetastatic niche. Cancer Res (in press)Google Scholar
  78. 78.
    Borges I, Sena I, Azevedo P, Andreotti J, Almeida V, Paiva A, Santos G, Guerra D, Prazeres P, Mesquita LL, de Barros Silva LS, Leonel C, Mintz A, Birbrair A (2017) Lung as a Niche for Hematopoietic Progenitors. Stem Cell Rev Rep 13(5):567–574CrossRefGoogle Scholar
  79. 79.
    Birbrair A (2017) Stem cell microenvironments and beyond. Adv Exp Med Biol 1041:1–3. CrossRefPubMedGoogle Scholar
  80. 80.
    Birbrair A, Frenette PS (2016) Niche heterogeneity in the bone marrow. Ann N Y Acad Sci 1370(1):82–96. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Lucas D (2017) The bone marrow microenvironment for hematopoietic stem cells. Adv Exp Med Biol 1041:5–18. CrossRefPubMedGoogle Scholar
  82. 82.
    Ramirez-Castillejo C, Sanchez-Sanchez F, Andreu-Agullo C, Ferron SR, Aroca-Aguilar JD, Sanchez P, Mira H, Escribano J, Farinas I (2006) Pigment epithelium-derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 9(3):331–339. CrossRefPubMedGoogle Scholar
  83. 83.
    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82. CrossRefGoogle Scholar
  84. 84.
    Sena IFG, Borges IT, Lousado L, Azevedo PO, Andreotti JP, Almeida VM, Paiva AE, Santos GSP, Guerra DAP, Prazeres PHDM, Souto L, Mintz A, Birbrair A (2017) LepR+ cells dispute hegemony with Gli1+ cells in bone marrow fibrosis. Cell Cycle 16(21):2018–2022CrossRefGoogle Scholar
  85. 85.
    Sena IFG, Prazeres PHDM, Santos GSP, Borges IT, Azevedo PO, Andreotti JP, Almeida VM, Paiva AE, Guerra DAP, Lousado L, Souto L, Mintz A, Birbrair A (2017) Identity of Gli1 + cells in the bone marrow. Experimental Hematology 54:12–16CrossRefGoogle Scholar
  86. 86.
    Bechmann I, Priller J, Kovac A, Bontert M, Wehner T, Klett FF, Bohsung J, Stuschke M, Dirnagl U, Nitsch R (2001) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14(10):1651–1658CrossRefGoogle Scholar
  87. 87.
    Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leuko Biol 75(3):388–397. CrossRefPubMedGoogle Scholar
  88. 88.
    Silva WN, Prazeres P, Paiva AE, Lousado L, Turquetti AOM, Barreto RSN, de Alvarenga EC, Miglino MA, Goncalves R, Mintz A, Birbrair A (2018) Macrophage-derived GPNMB accelerates skin healing. Exp dermatol. CrossRefPubMedGoogle Scholar
  89. 89.
    Crisan M, Corselli M, Chen WC, Peault B (2012) Perivascular cells for regenerative medicine. J Cell Mol Med. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Soderblom C, Luo X, Blumenthal E, Bray E, Lyapichev K, Ramos J, Krishnan V, Lai-Hsu C, Park KK, Tsoulfas P, Lee JK (2013) Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci 33(34):13882–13887. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Lousado L, Prazeres PHDM, Andreotti JP, Paiva AE, Azevedo PO, Santos GSP, Filev R, Mintz A, Birbrair A (2017) Schwann cell precursors as a source for adrenal gland chromaffin cells. Cell Death Dis 8(10):e3072CrossRefGoogle Scholar
  92. 92.
    Dahl D, Zapatka S, Bignami A (1986) Heterogeneity of desmin, the muscle-type intermediate filament protein, in blood vessels and astrocytes. Histochemistry 84(2):145–150CrossRefGoogle Scholar
  93. 93.
    Choi JH, Riew TR, Kim HL, Jin X, Lee MY (2017) Desmin expression profile in reactive astrocytes in the 3-nitropropionic acid-lesioned striatum of rat: characterization and comparison with glial fibrillary acidic protein and nestin. Acta Histochem 119(8):795–803. CrossRefPubMedGoogle Scholar
  94. 94.
    Andreotti JP, Prazeres PHDM, Magno LAV, Romano-Silva MA, Mintz A, Birbrair A (2018) Neurogenesis in the postnatal cerebellum after injury. Int J Dev Neurosci 67:33–36CrossRefGoogle Scholar
  95. 95.
    Pruimboom-Brees IM, Brees DJ, Shen AC, Ibebunjo C (2004) Malignant astrocytoma with binucleated granular cells in a Sprague-Dawley rat. Vet Pathol 41(3):287–290. CrossRefPubMedGoogle Scholar
  96. 96.
    Dias Moura Prazeres PH, Sena IFG, Borges IDT, de Azevedo PO, Andreotti JP, de Paiva AE, de Almeida VM, de Paula Guerra DA, Pinheiro Dos Santos GS, Mintz A, Delbono O, Birbrair A (2017) Pericytes are heterogeneous in their origin within the same tissue. Dev Biol 427(1):6–11. CrossRefPubMedGoogle Scholar
  97. 97.
    Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar JC, Bergman A, Frenette PS (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502(7473):637–643. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Nehls V, Denzer K, Drenckhahn D (1992) Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270(3):469–474CrossRefGoogle Scholar
  100. 100.
    Birbrair A, Wang ZM, Messi ML, Enikolopov GN, Delbono O, Rota M (2011) Nestin-GFP Transgene Reveals Neural Precursor Cells in Adult Skeletal Muscle. PLoS ONE 6(2):e16816CrossRefGoogle Scholar
  101. 101.
    Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J (2011) A pericyte origin of spinal cord scar tissue. Science 333(6039):238–242. CrossRefGoogle Scholar
  102. 102.
    Kaukonen J, Lahtinen I, Laine S, Alitalo K, Palotie A (1996) BMX tyrosine kinase gene is expressed in granulocytes and myeloid leukaemias. Br J Haematol 94(3):455–460PubMedGoogle Scholar
  103. 103.
    Guryanova OA, Wu Q, Cheng L, Lathia JD, Huang Z, Yang J, MacSwords J, Eyler CE, McLendon RE, Heddleston JM, Shou W, Hambardzumyan D, Lee J, Hjelmeland AB, Sloan AE, Bredel M, Stark GR, Rich JN, Bao S (2011) Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell 19(4):498–511. CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Andreotti JP, Lousado L, Magno LAV, Birbrair A (2017) Hypothalamic neurons take center stage in the neural stem cell niche. Cell Stem Cell 21(3):293–294. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Guerra DAP, Paiva AE, Sena IFG, Azevedo PO, Batista ML Jr, Mintz A, Birbrair A (2017) Adipocytes role in the bone marrow niche. Cytom Part A. CrossRefGoogle Scholar
  106. 106.
    Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ (2010) The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 107(29):13075–13080. CrossRefPubMedGoogle Scholar
  107. 107.
    Leong DP, Caron F, Hillis C, Duan A, Healey JS, Fraser G, Siegal D (2016) The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood 128(1):138–140. CrossRefGoogle Scholar
  108. 108.
    Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, DeVos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC (2018) Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia 32(1):83–91. CrossRefPubMedGoogle Scholar
  109. 109.
    Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O’Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ, Investigators R- (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373(25):2425–2437. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P, Investigators R (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371(3):213–223. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Osterborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S (2016) Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 17(10):1409–1418. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Department of RadiologyColumbia University Medical CenterNew YorkUSA

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