Advertisement

Pericytes for Therapeutic Bone Repair

  • Carolyn A. Meyers
  • Joan Casamitjana
  • Leslie Chang
  • Lei Zhang
  • Aaron W. James
  • Bruno Péault
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1109)

Abstract

Besides seminal functions in angiogenesis and blood pressure regulation, microvascular pericytes possess a latent tissue regenerative potential that can be revealed in culture following transition into mesenchymal stem cells. Endowed with robust osteogenic potential, pericytes and other related perivascular cells extracted from adipose tissue represent a potent and abundant cell source for refined bone tissue engineering and improved cell therapies of fractures and other bone defects. The use of diverse bone formation assays in vivo, which include mouse muscle pocket osteogenesis and calvaria replenishment, rat and dog spine fusion, and rat non-union fracture healing, has confirmed the superiority of purified perivascular cells for skeletal (re)generation. As a surprising observation though, despite strong endogenous bone-forming potential, perivascular cells drive bone regeneration essentially indirectly, via recruitment by secreted factors of local osteo-progenitors.

Keywords

Pericyte Blood vessel Osteogenesis Mesenchymal stem cell Bone Spinal fusion Non-union Tunica adventitia Perivascular cell Stem cell 

Notes

Acknowledgments

The present work was supported by the NIH/NIAMS (R01 AR070773, K08 AR068316), NIH/NIDCR (R21 DE027922), USAMRAA through the Peer Reviewed Medical Research Program (W81XWH-180109121, PR170115), and Department of Defense through the Broad Agency Announcement (BA160256), American Cancer Society (Research Scholar Grant, RSG-18-027-01-CSM), the Maryland Stem Cell Research Foundation, the Musculoskeletal Transplant Foundation, the California Institute for Regenerative Medicine, the British Heart Foundation, and Medical Research Council.

References

  1. 1.
    Diaz-Flores L, Gutierrez R, Gonzalez P, Varela H (1991) Inducible perivascular cells contribute to the neochondrogenesis in grafted perichondrium. Anat Rec 229(1):1–8.  https://doi.org/10.1002/ar.1092290102CrossRefPubMedGoogle Scholar
  2. 2.
    Zimmermann KW (1923) Der feinere Bau der Blutkapillaren. Z Anat 68:29–109CrossRefGoogle Scholar
  3. 3.
    Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23 Epub 2003 Jul 22CrossRefPubMedGoogle Scholar
  4. 4.
    Stallcup WB, You WK, Kucharova K, Cejudo-Martin P, Yotsumoto F (2016) NG2 proteoglycan-dependent contributions of pericytes and macrophages to brain tumor vascularization and progression. Microcirculation 23(2):122–133.  https://doi.org/10.1111/micc.12251CrossRefPubMedGoogle Scholar
  5. 5.
    Ross R, Everett NB, Tyler R (1970) Wound healing and collagen formation. VI. The origin of the wound fibroblast studied in parabiosis. J Cell Biol 44(3):645–654 PMID: 5415241 PMCID: PMC2107958CrossRefPubMedGoogle Scholar
  6. 6.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313CrossRefPubMedGoogle Scholar
  7. 7.
    Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE (2004) Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110(15):2226–2232 Epub 2004 Oct 4CrossRefPubMedGoogle Scholar
  8. 8.
    Lin G, Garcia M, Ning H, Banie L, Guo YL, Lue TF, Lin CS (2008) Defining stem and progenitor cells within adipose tissue. Stem Cells Dev 17(6):1053–1063.  https://doi.org/10.1089/scd.2008.0117CrossRefPubMedGoogle Scholar
  9. 9.
    Chen WC, Baily JE, Corselli M, Díaz ME, Sun B, Xiang G, Gray GA, Huard J, Péault B (2015) Human myocardial pericytes: multipotent mesodermal precursors exhibiting cardiac specificity. Stem Cells 33(2):557–573.  https://doi.org/10.1002/stem.1868CrossRefPubMedGoogle Scholar
  10. 10.
    Murray IR, Gonzalez ZN, Baily J, Dobie R, Wallace RJ, Mackinnon AC, Smith JR, Greenhalgh SN, Thompson AI, Conroy KP, Griggs DW, Ruminski PG, Gray GA, Singh M, Campbell MA, Kendall TJ, Dai J, Li Y, Iredale JP, Simpson H, Huard J, Péault B, Henderson NC (2017) αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nat Commun 8(1):1118.  https://doi.org/10.1038/s41467-017-01097-zCrossRefPubMedGoogle Scholar
  11. 11.
    Shaw I, Rider S, Mullins J, Hughes J, Péault B (2018) Pericytes in the renal vasculature: roles in health and disease. Nat Rev Nephrol 14(8):521–534.  https://doi.org/10.1038/s41581-018-0032-4CrossRefPubMedGoogle Scholar
  12. 12.
    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.  https://doi.org/10.1038/nature12612CrossRefPubMedGoogle Scholar
  13. 13.
    Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481(7382):457–462.  https://doi.org/10.1038/nature10783CrossRefPubMedGoogle Scholar
  14. 14.
    Corselli M, Chin CJ, Parekh C, Sahaghian A, Wang W, Ge S, Evseenko D, Wang X, Montelatici E, Lazzari L, Crooks GM, Péault B (2013) Perivascular support of human hematopoietic stem/progenitor cells. Blood 121(15):2891–2901.  https://doi.org/10.1182/blood-2012-08-451864CrossRefPubMedGoogle Scholar
  15. 15.
    Sá da Bandeira D, Casamitjana J, Crisan M (2017) Pericytes, integral components of adult hematopoietic stem cell niches. Pharmacol Ther 171:104–113.  https://doi.org/10.1016/j.pharmthera.2016.11.006 Epub 2016 Nov 28CrossRefPubMedGoogle Scholar
  16. 16.
    Chin CJ, Li S, Corselli M, Casero D, Zhu Y, He CB, Hardy R, Péault B, Crooks GM (2018) Transcriptionally and functionally distinct mesenchymal subpopulations are generated from human pluripotent stem cells. Stem Cell Reports 10(2):436–446.  https://doi.org/10.1016/j.stemcr.2017.12.005CrossRefPubMedGoogle Scholar
  17. 17.
    Meyers CA, Xu J, Zhang L, Asatrian G, Ding C, Yan N, Broderick K, Sacks J, Goyal R, Zhang X, Ting K, Peault B, Soo C, James AW (2018) Early immunomodulatory effects of implanted human perivascular stromal cells during bone formation. Tissue Eng Part A 24(5–6):448–457.  https://doi.org/10.1089/ten.TEA.2017.0023CrossRefPubMedGoogle Scholar
  18. 18.
    James AW, Zara JN, Corselli M, Chiang M, Yuan W, Nguyen V, Askarinam A, Goyal R, Siu RK, Scott V, Lee M, Ting K, Péault B, Soo C (2012) Use of human perivascular stem cells for bone regeneration. J Vis Exp (63):e2952.  https://doi.org/10.3791/2952 PubMed PMID: 22664543; PMCID: PMC3466949
  19. 19.
    Diaz-Flores L, Gutierrez R, Lopez-Alonso A, Gonzalez R, Varela H (1992) Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin Orthop Relat Res 275:280–286 PubMed PMID: 1735226Google Scholar
  20. 20.
    Matthews BG, Grcevic D, Wang L, Hagiwara Y, Roguljic H, Joshi P, Shin DG, Adams DJ, Kalajzic I (2014) Analysis of alphaSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing. J Bone Miner Res 29(5):1283–1294.  https://doi.org/10.1002/jbmr.2140 PubMed PMID: 24190076; PMCID: PMC4864015CrossRefPubMedGoogle Scholar
  21. 21.
    Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, Bianco P (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131(2):324–336. PMID: 17956733.  https://doi.org/10.1016/j.cell.2007.08.025CrossRefPubMedGoogle Scholar
  22. 22.
    Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, Cossu G, Serafini M, Sampaolesi M, Tagliafico E, Tenedini E, Saggio I, Robey PG, Riminucci M, Bianco P (2016) No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Reports 6(6):897–913.  https://doi.org/10.1016/j.stemcr.2016.05.011CrossRefPubMedGoogle Scholar
  23. 23.
    James AW, Hindle P, Murray IR, West CC, Tawonsawatruk T, Shen J, Asatrian G, Zhang X, Nguyen V, Simpson AH, Ting K, Soo C (2017) Pericytes for the treatment of orthopedic conditions. Pharmacol Ther 171:93–103.  https://doi.org/10.1016/j.pharmthera.2016.08.003CrossRefGoogle Scholar
  24. 24.
    Mravic M, Asatrian G, Soo C, Lugassy C, Barnhill RL, Dry SM, Peault B, James AW (2014) From pericytes to perivascular tumours: correlation between pathology, stem cell biology, and tissue engineering. Int Orthop 38(9):1819–1824.  https://doi.org/10.1007/s00264-014-2295-0CrossRefGoogle Scholar
  25. 25.
    Sers C, Riethmüller G, Johnson JP (1994) MUC18, a melanoma-progression associated molecule, and its potential role in tumor vascularization and hematogenous spread. Cancer Res 54(21):5689–5694 PMID: 7923217PubMedGoogle Scholar
  26. 26.
    Tormin A, Li O, Brune JC, Walsh S, Schütz B, Ehinger M, Ditzel N, Kassem M, Scheding S (2011) CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood 117(19):5067–5077.  https://doi.org/10.1182/blood-2010-08-304287CrossRefPubMedGoogle Scholar
  27. 27.
    Covas DT, Panepucci RA, Fontes AM, Silva WA Jr, Orellana MD, Freitas MC, Neder L, Santos AR, Peres LC, Jamur MC, Zago MA (2008) Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol 36(5):642–654.  https://doi.org/10.1016/j.exphem.2007.12.015CrossRefPubMedGoogle Scholar
  28. 28.
    Shih IM (1999) The role of CD146 (Mel-CAM) in biology and pathology. J Pathol 189(1):4–11. PMID: 10451481.  https://doi.org/10.1002/(SICI)1096-9896(199909)189:1<4::AID-PATH332>3.0.CO;2-PCrossRefPubMedGoogle Scholar
  29. 29.
    James AW, Zara JN, Zhang X, Askarinam A, Goyal R, Chiang M, Yuan W, Chang L, Corselli M, Shen J, Pang S, Stoker D, Wu B, Ting K, Peault B, Soo C (2012) Perivascular stem cells: a prospectively purified mesenchymal stem cell population for bone tissue engineering. Stem Cells Transl Med 1(6):510–519.  https://doi.org/10.5966/sctm.2012-0002 PubMed PMID: 23197855; PMCID: PMC3659717CrossRefPubMedGoogle Scholar
  30. 30.
    West CC, Hardy WR, Murray IR, James AW, Corselli M, Pang S, Black C, Lobo SE, Sukhija K, Liang P, Lagishetty V, Hay DC, March KL, Ting K, Soo C, Péault B (2016) Prospective purification of perivascular presumptive mesenchymal stem cells from human adipose tissue: process optimization and cell population metrics across a large cohort of diverse demographics. Stem Cell Res Ther 7:47.  https://doi.org/10.1186/s13287-016-0302-7 PubMed PMID: 27029948; PMCID: PMC4815276CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang X, Péault B, Chen W, Li W, Corselli M, James AW, Lee M, Siu RK, Shen P, Zheng Z, Shen J, Kwak J, Zara JN, Chen F, Zhang H, Yin Z, Wu B, Ting K, Soo C (2011) The Nell-1 growth factor stimulates bone formation by purified human perivascular cells. Tissue Eng Part A 17(19–20):2497–2509.  https://doi.org/10.1089/ten.TEA.2010.0705 PubMed PMID: 21615216; PMCID: PMC3179623CrossRefPubMedGoogle Scholar
  32. 32.
    Corselli M, Chen CW, Sun B, Yap S, Rubin JP, Peault B (2012) The tunica adventitia of human arteries and veins as a source of mesenchymal stem cells. Stem Cells Dev 21(8):1299–1308.  https://doi.org/10.1089/scd.2011.0200. Epub 2011/08/25. PubMed PMID: 21861688; PMCID: 3353742CrossRefPubMedGoogle Scholar
  33. 33.
    James AW, Zara JN, Corselli M, Askarinam A, Zhou AM, Hourfar A, Nguyen A, Megerdichian S, Asatrian G, Pang S, Stoker D, Zhang X, Wu B, Ting K, Peault B, Soo C (2012) An abundant perivascular source of stem cells for bone tissue engineering. Stem Cells Transl Med 1(9):673–684. Epub 2012/12/01.  https://doi.org/10.5966/sctm.2012-0053CrossRefPubMedGoogle Scholar
  34. 34.
    Hardy WR, Moldovan NI, Moldovan L, Livak KJ, Datta K, Goswami C, Corselli M, Traktuev DO, Murray IR, Peault B, March K (2017) Transcriptional networks in single perivascular cells sorted from human adipose tissue reveal a hierarchy of mesenchymal stem cells. Stem Cells 35(5):1273–1289.  https://doi.org/10.1002/stem.2599CrossRefPubMedGoogle Scholar
  35. 35.
    Zimmerlin L, Donnenberg VS, Pfeifer ME, Meyer EM, Péault B, Rubin JP, Donnenberg AD (2010) Stromal vascular progenitors in adult human adipose tissue. Cytometry A 77(1):22–30.  https://doi.org/10.1002/cyto.a.20813CrossRefPubMedGoogle Scholar
  36. 36.
    Park TS, Gavina M, Chen CW, Sun B, Teng PN, Huard J, Deasy BM, Zimmerlin L, Péault B (2011) Placental perivascular cells for human muscle regeneration. Stem Cells Dev 20(3):451–463.  https://doi.org/10.1089/scd.2010.0354CrossRefPubMedGoogle Scholar
  37. 37.
    Gerlach JC, Over P, Turner ME, Thompson RL, Foka HG, Chen WC, Péault B, Gridelli B, Schmelzer E (2012) Perivascular mesenchymal progenitors in human fetal and adult liver. Stem Cells Dev 21(18):3258–3269.  https://doi.org/10.1089/scd.2012.0296CrossRefPubMedGoogle Scholar
  38. 38.
    Askarinam A, James AW, Zara JN, Goyal R, Corselli M, Pan A, Liang P, Chang L, Rackohn T, Stoker D, Zhang X, Ting K, Peault B, Soo C (2013) Human perivascular stem cells show enhanced osteogenesis and vasculogenesis with Nel-like molecule I protein. Tissue Eng Part A 19(11–12):1386–1397.  https://doi.org/10.1089/ten.TEA.2012.0367 Epub 2013/02/15. PubMed PMID: 23406369; PMCID: 3638559CrossRefPubMedGoogle Scholar
  39. 39.
    Hindle P, Khan N, Biant L, Péault B (2017) The infrapatellar fat pad as a source of perivascular stem cells with increased chondrogenic potential for regenerative medicine. Stem Cells Transl Med 6(1):77–87.  https://doi.org/10.5966/sctm.2016-0040CrossRefPubMedGoogle Scholar
  40. 40.
    Stefanska A, Kenyon C, Christian HC, Buckley C, Shaw I, Mullins JJ, Péault B (2016) Human kidney pericytes produce renin. Kidney Int 90(6):1251–1261.  https://doi.org/10.1016/j.kint.2016.07.035CrossRefPubMedGoogle Scholar
  41. 41.
    Eliasberg CD, Dar A, Jensen AR, Murray IR, Hardy WR, Kowalski TJ, Garagozlo CA, Natsuhara KM, Khan AZ, McBride OJ, Cha PI, Kelley BV, Evseenko D, Feeley BT, McAllister DR, Péault B, Petrigliano FA (2017) Perivascular stem cells diminish muscle atrophy following massive rotator cuff tears in a small animal model. J Bone Joint Surg Am 99(4):331–341.  https://doi.org/10.2106/JBJS.16.00645CrossRefPubMedGoogle Scholar
  42. 42.
    James AW, Zhang X, Crisan M, Hardy WR, Liang P, Meyers CA, Lobo S, Lagishetty V, Childers MK, Asatrian G, Ding C, Yen YH, Zou E, Ting K, Peault B, Soo C (2017) Isolation and characterization of canine perivascular stem/stromal cells for bone tissue engineering. PLoS One 12(5):e0177308.  https://doi.org/10.1371/journal.pone.0177308CrossRefPubMedGoogle Scholar
  43. 43.
    Hindle P, Baily J, Khan N, Biant LC, Simpson AH, Péault B (2016) Perivascular mesenchymal stem cells in sheep: characterization and autologous transplantation in a model of articular cartilage repair. Stem Cells Dev 25(21):1659–1669.  https://doi.org/10.1089/scd.2016.0165 Epub 2016 Aug 23CrossRefPubMedGoogle Scholar
  44. 44.
    Esteves CL, Sheldrake TA, Mesquita SP, Pesántez JJ, Menghini T, Dawson L, Péault B, Donadeu FX (2017) Isolation and characterization of equine native MSC populations. Stem Cell Res Ther 8(1):80.  https://doi.org/10.1186/s13287-017-0525-2CrossRefPubMedGoogle Scholar
  45. 45.
    Esteves CL, Sheldrake TA, Dawson L, Menghini T, Rink BE, Amilon K, Khan N, Péault B, Donadeu FX (2017) Equine mesenchymal stromal cells retain a pericyte-like phenotype. Stem Cells Dev 26(13):964–972.  https://doi.org/10.1089/scd.2017.0017CrossRefPubMedGoogle Scholar
  46. 46.
    Chung CG, James AW, Asatrian G, Chang L, Nguyen A, Le K, Bayani G, Lee R, Stoker D, Pang S, Zhang X, Ting K, Peault B, Soo C (2015) Human perivascular stem cell-based bone graft substitute induces rat spinal fusion. Stem Cells Transl Med 4(5):538.  https://doi.org/10.5966/sctm.2014-0027erratum PubMed PMID: 25926331; PMCID: PMC4414212CrossRefPubMedGoogle Scholar
  47. 47.
    Lee S, Zhang X, Shen J, James AW, Chung CG, Hardy R, Li C, Girgius C, Zhang Y, Stoker D, Wang H, Wu BM, Peault B, Ting K, Soo C (2015) Brief report: human perivascular stem cells and Nel-like Protein-1 synergistically enhance spinal fusion in osteoporotic rats. Stem Cells 33(10):3158–3163.  https://doi.org/10.1002/stem.2103 PubMed PMID: 26173400; PMCID: PMC4831713CrossRefPubMedGoogle Scholar
  48. 48.
    Reed AA, Joyner CJ, Isefuku S, Brownlow HC, Simpson AH (2003) Vascularity in a new model of atrophic nonunion. J Bone Joint Surg (Br) 85(4):604–610CrossRefGoogle Scholar
  49. 49.
    Bajada S, Marshall MJ, Wright KT, Richardson JB, Johnson WE (2009) Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells. Bone 45(4):726–735.  https://doi.org/10.1016/j.bone.2009.06.015CrossRefPubMedGoogle Scholar
  50. 50.
    Tawonsawatruk T, West CC, Murray IR, Soo C, Péault B, Simpson H (2016) Adipose derived pericytes rescue fractures from a failure of healing – non-union. Sci Rep 6:22779CrossRefPubMedGoogle Scholar
  51. 51.
    Chapelin F, Khurana A, Moneeb M, Gray Hazard FK, Chan CFR, Nejadnik H, Gratzinger D, Messing S, Erdmann J, Gaur A, Daldrup-Link HE (2018) Tumor formation of adult stem cell transplants in rodent arthritic joints. Mol Imaging Biol.  https://doi.org/10.1007/s11307-018-1218-7
  52. 52.
    Lee HY, Hong IS (2017) Double-edged sword of mesenchymal stem cells: cancer-promoting versus therapeutic potential. Cancer Sci 108(10):1939–1946CrossRefPubMedGoogle Scholar
  53. 53.
    Alakpa E, Jayawarna V, Burgess K, West CC, Bakker S, Roy S, Javid N, Fleming S, Lamprou D, Yang J, Miller A, Urquhart A, Frederix P, Hunt N, Peault B, Ulijn RV, Dalby M (2016) Tuneable supramolecular hydrogels for selection of lineage guiding metabolites in stem cell cultures. Chem (Cell) 1:1–22Google Scholar
  54. 54.
    Kramann R, Goettsch C, Wongboonsin J, Iwata H, Schneider RK, Kuppe C, Kaesler N, Chang-Panesso M, Machado FG, Gratwohl S, Madhurima K, Hutcheson JD, Jain S, Aikawa E, Humphreys BD (2016) Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease. Cell Stem Cell 19(5):628–642CrossRefPubMedGoogle Scholar
  55. 55.
    Caplan AI (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl Med 6(6):1445–1451.  https://doi.org/10.1002/sctm.17-0051CrossRefPubMedGoogle Scholar
  56. 56.
    Dickinson SC, Sutton CA, Williams RL, West CC, Evseenko D, Wu L, Brady K, Pang S, Ferro de Godoy R, Goodship AE, Péault B, Blom AW, Kafienah W, Hollander AP (2017) The Wnt5a receptor ROR2 is a predictive cell surface marker of human mesenchymal stem cells with an enhanced capacity for chondrogenic differentiation. Stem Cells 35(11):2280–2291.  https://doi.org/10.1002/stem.2691CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Carolyn A. Meyers
    • 1
  • Joan Casamitjana
    • 2
  • Leslie Chang
    • 1
  • Lei Zhang
    • 1
  • Aaron W. James
    • 1
    • 3
  • Bruno Péault
    • 2
    • 3
  1. 1.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  2. 2.MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUK
  3. 3.Orthopaedic Hospital Research CenterUniversity of CaliforniaLos AngelesUSA

Personalised recommendations