Top

Published in:

Open Access 01-07-2019 | Type 2 Diabetes | Article

Bone marrow pericyte dysfunction in individuals with type 2 diabetes

Authors: Giuseppe Mangialardi, David Ferland-McCollough, Davide Maselli, Marianna Santopaolo, Andrea Cordaro, Gaia Spinetti, Maria Sambataro, Niall Sullivan, Ashley Blom, Paolo Madeddu

Published in: Diabetologia | Issue 7/2019

Abstract

Aims/hypothesis

Previous studies have shown that diabetes mellitus destabilises the integrity of the microvasculature in different organs by damaging the interaction between pericytes and endothelial cells. In bone marrow, pericytes exert trophic functions on endothelial cells and haematopoietic cells through paracrine mechanisms. However, whether bone marrow pericytes are a target of diabetes-induced damage remains unknown. Here, we investigated whether type 2 diabetes can affect the abundance and function of bone marrow pericytes.

Methods

We conducted an observational clinical study comparing the abundance and molecular/functional characteristics of CD146⁺ pericytes isolated from the bone marrow of 25 individuals without diabetes and 14 individuals with uncomplicated type 2 diabetes, referring to our Musculoskeletal Research Unit for hip reconstructive surgery.

Results

Immunohistochemistry revealed that diabetes causes capillary rarefaction and compression of arteriole size in bone marrow, without changing CD146⁺ pericyte counts. These data were confirmed by flow cytometry on freshly isolated bone marrow cells. We then performed an extensive functional and molecular characterisation of immunosorted CD146⁺ pericytes. Type 2 diabetes caused a reduction in pericyte proliferation, viability, migration and capacity to support in vitro angiogenesis, while inducing apoptosis. AKT is a key regulator of the above functions and its phosphorylation state is reportedly reduced in the bone marrow endothelium of individuals with diabetes. Surprisingly, we could not find a difference in AKT phosphorylation (at either Ser473 or Thr308) in bone marrow pericytes from individuals with and without diabetes. Nonetheless, the angiocrine signalling reportedly associated with AKT was found to be significantly downregulated, with lower levels of fibroblast growth factor-2 (FGF2) and C-X-C motif chemokine ligand 12 (CXCL12), and activation of the angiogenesis inhibitor angiopoietin 2 (ANGPT2). Transfection with the adenoviral vector carrying the coding sequence for constitutively active myristoylated AKT rescued functional defects and angiocrine signalling in bone marrow pericytes from diabetic individuals. Furthermore, an ANGPT2 blocking antibody restored the capacity of pericytes to promote endothelial networking.

Conclusions/interpretation

This is the first demonstration of pericyte dysfunction in bone marrow of people with type 2 diabetes. An altered angiocrine signalling from pericytes may participate in bone marrow microvascular remodelling in individuals with diabetes.

Available only for authorised users

Beckman JA, Paneni F, Cosentino F, Creager MA (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Eur Heart J 34(31):2444–2452. https://doi.org/10.1093/eurheartj/eht142 CrossRefPubMed

Hossain P, Kawar B, El Nahas M (2007) Obesity and diabetes in the developing world--a growing challenge. N Engl J Med 356(3):213–215. https://doi.org/10.1056/NEJMp068177 CrossRef

Paneni F, Costantino S, Volpe M, Luscher TF, Cosentino F (2013) Epigenetic signatures and vascular risk in type 2 diabetes: a clinical perspective. Atherosclerosis 230(2):191–197. https://doi.org/10.1016/j.atherosclerosis.2013.07.003 CrossRefPubMed

Fadini GP, Ciciliot S, Albiero M (2017) Concise review: perspectives and clinical implications of bone marrow and circulating stem cell defects in diabetes. Stem Cells 35(1):106–116. https://doi.org/10.1002/stem.2445 CrossRefPubMed

Mangialardi G, Madeddu P (2016) Bone marrow-derived stem cells: a mixed blessing in the multifaceted world of diabetic complications. Curr Diab Rep 16(5):43. https://doi.org/10.1007/s11892-016-0730-x CrossRefPubMedPubMedCentral

Mangialardi G, Oikawa A, Reni C, Madeddu P (2012) Bone marrow microenvironment: a newly recognized target for diabetes-induced cellular damage. Endocr Metab Immune Disord Drug Targets 12(2):159–167. https://doi.org/10.2174/187153012800493530 CrossRefPubMed

Dang Z, Maselli D, Spinetti G et al (2015) Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes. Diabetologia 58(11):2653–2662. https://doi.org/10.1007/s00125-015-3735-0 CrossRefPubMedPubMedCentral

Fadini GP, Agostini C, Sartore S, Avogaro A (2007) Endothelial progenitor cells in the natural history of atherosclerosis. Atherosclerosis 194(1):46–54. https://doi.org/10.1016/j.atherosclerosis.2007.03.046 CrossRefPubMed

Patel RS, Li QN, Ghasemzadeh N et al (2015) Circulating CD34(+) progenitor cells and risk of mortality in a population with coronary artery disease. Circ Res 116(2):289–U235. https://doi.org/10.1161/Circresaha.116.304187 CrossRefPubMed

10.

Rigato M, Avogaro A, Fadini GP (2016) Levels of circulating progenitor cells, cardiovascular outcomes and death: a meta-analysis of prospective observational studies. Circ Res 118(12):1930–1939. https://doi.org/10.1161/CIRCRESAHA.116.308366 CrossRefPubMed

11.

Oikawa A, Siragusa M, Quaini F et al (2010) Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol 30(3):498–508. https://doi.org/10.1161/ATVBAHA.109.200154 CrossRefPubMed

12.

Spinetti G, Cordella D, Fortunato O et al (2013) Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res 112(3):510–522. https://doi.org/10.1161/CIRCRESAHA.112.300598 CrossRefPubMed

13.

Reni C, Mangialardi G, Meloni M, Madeddu P (2016) Diabetes stimulates osteoclastogenesis by acidosis-induced activation of transient receptor potential cation channels. Sci Rep 6(1):30639. https://doi.org/10.1038/srep30639 CrossRefPubMedPubMedCentral

14.

Ferland-McCollough D, Masseli D, Spinetti G et al (2018) MCP-1 feedback loop between adipocytes and mesenchymal stromal cells causes fat accumulation and contributes to hematopoietic stem cell rarefaction in the bone marrow of diabetic patients. Diabetes 67(7):1380–1394. https://doi.org/10.2337/db18-0044 CrossRefPubMed

15.

Mangialardi G, Katare R, Oikawa A et al (2013) Diabetes causes bone marrow endothelial barrier dysfunction by activation of the RhoA-Rho-associated kinase signaling pathway. Arterioscler Thromb Vasc Biol 33(3):555–564. https://doi.org/10.1161/ATVBAHA.112.300424 CrossRefPubMedPubMedCentral

16.

Mangialardi G, Spinetti G, Reni C, Madeddu P (2014) Reactive oxygen species adversely impacts bone marrow microenvironment in diabetes. Antioxid Redox Signal 21(11):1620–1633. https://doi.org/10.1089/ars.2014.5944 CrossRefPubMedPubMedCentral

17.

Pfister F, Przybyt E, Harmsen MC, Hammes HP (2013) Pericytes in the eye. Pflugers Arch 465(6):789–796. https://doi.org/10.1007/s00424-013-1272-6 CrossRefPubMed

18.

Price TO, Sheibani N, Shah GN (2017) Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: a specific target for prevention of diabetic cerebrovascular pathology. Biochim Biophys Acta Mol basis Dis 1863(4):929–935. https://doi.org/10.1016/j.bbadis.2017.01.025 CrossRefPubMed

19.

Mangialardi G, Cordaro A, Madeddu P (2016) The bone marrow pericyte: an orchestrator of vascular niche. Regen Med 11(8):883–895. https://doi.org/10.2217/rme-2016-0121 CrossRefPubMedPubMedCentral

20.

Sa 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 CrossRefPubMed

21.

Sivaraj KK, Adams RH (2016) Blood vessel formation and function in bone. Development 143(15):2706–2715. https://doi.org/10.1242/dev.136861 CrossRefPubMed

22.

Zhou BO, Yue R, Murphy MM, Peyer JG, Morrison SJ (2014) Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15(2):154–168. https://doi.org/10.1016/j.stem.2014.06.008 CrossRefPubMedPubMedCentral

23.

Tormin A, Li O, Brune JC et al (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-2010-08-304287 CrossRefPubMedPubMedCentral

24.

Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25(6):977–988. https://doi.org/10.1016/j.immuni.2006.10.016 CrossRefPubMed

25.

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/nature10783 CrossRefPubMedPubMedCentral

26.

Mendez-Ferrer S, Michurina TV, Ferraro F et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–U859. https://doi.org/10.1038/nature09262 CrossRefPubMedPubMedCentral

27.

Sacchetti B, Funari A, Michienzi S et al (2008) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 133(5):928–928. https://doi.org/10.1016/j.cell.2008.05.015 CrossRef

28.

Corselli M, Chin CJ, Parekh C et al (2013) Perivascular support of human hematopoietic stem/progenitor cells. Blood 121(15):2891–2901. https://doi.org/10.1182/blood-2012-08-451864 CrossRefPubMedPubMedCentral

29.

Mendelson A, Frenette PS (2014) Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20(8):833–846. https://doi.org/10.1038/nm.3647 CrossRefPubMedPubMedCentral

30.

Ugarte F, Forsberg EC (2013) Haematopoietic stem cell niches: new insights inspire new questions. EMBO J 32(19):2535–2547. https://doi.org/10.1038/emboj.2013.201 CrossRefPubMedPubMedCentral

31.

Asada N, Kunisaki Y, Pierce H et al (2017) Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol 19(3):214–223. https://doi.org/10.1038/ncb3475 CrossRefPubMedPubMedCentral

32.

Oguro H, Ding L, Morrison SJ (2013) SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell 13(1):102–116. https://doi.org/10.1016/j.stem.2013.05.014 CrossRefPubMedPubMedCentral

33.

Sacchetti B, Funari A, Remoli C et al (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 Rep 6(6):897–913. https://doi.org/10.1016/j.stemcr.2016.05.011 CrossRef

34.

Spinetti G, Kraenkel N, Emanueli C, Madeddu P (2008) Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovasc Res 78(2):265–273. https://doi.org/10.1093/cvr/cvn039 CrossRefPubMedPubMedCentral

35.

Azar WJ, Azar SH, Higgins S et al (2011) IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology 152(9):3332–3342. https://doi.org/10.1210/en.2011-1121 CrossRefPubMed

36.

Sawamiphak S, Seidel S, Essmann CL et al (2010) Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465(7297):487–491. https://doi.org/10.1038/nature08995 CrossRefPubMed

37.

Sainson RC, Harris AL (2008) Regulation of angiogenesis by homotypic and heterotypic notch signalling in endothelial cells and pericytes: from basic research to potential therapies. Angiogenesis 11(1):41–51. https://doi.org/10.1007/s10456-008-9098-0 CrossRefPubMed

38.

Roth L, Prahst C, Ruckdeschel T et al (2016) Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. Sci Signal 9(425):ra42. https://doi.org/10.1126/scisignal.aad3812 CrossRefPubMed

39.

Ochsenbein AM, Karaman S, Proulx ST et al (2016) Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells. Development 143(4):589–594. https://doi.org/10.1242/dev.127670 CrossRefPubMed

40.

Urbich C, Kaluza D, Fromel T et al (2012) MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood 119(6):1607–1616. https://doi.org/10.1182/blood-2011-08-373886 CrossRefPubMed

41.

Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G (2001) Mammalian sprouty-1 and-2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 152(5):1087–1098. https://doi.org/10.1083/jcb.152.5.1087 CrossRefPubMedPubMedCentral

42.

Haviv F, Bradley MF, Kalvin DM et al (2005) Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. J Med Chem 48(8):2838–2846. https://doi.org/10.1021/jm0401560 CrossRefPubMed

43.

Kobayashi H, Butler JM, O’Donnell R et al (2010) Angiocrine factors from Aktactivated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12(11):1046–1056. https://doi.org/10.1038/ncb2108 CrossRefPubMedPubMedCentral

44.

Rafii S, Butler JM, Ding BS (2016) Angiocrine functions of organ-specific endothelial cells. Nature 529(7586):316–325. https://doi.org/10.1038/nature17040 CrossRefPubMedPubMedCentral

45.

Ju R, Zhuang ZW, Zhang J et al (2014) Angiopoietin-2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan-4/syntenin pathways. J Biol Chem 289(1):510–519. https://doi.org/10.1074/jbc.M113.506899 CrossRefPubMed

46.

Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314(1):15–23. https://doi.org/10.1007/s00441-003-0745-x CrossRefPubMed

47.

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. https://doi.org/10.1161/01.CIR.0000144457.55518.E5 CrossRefPubMed

48.

Lin G, Garcia M, Ning H et al (2008) Defining stem and progenitor cells within adipose tissue. Stem Cells Dev 17(6):1053–1063. https://doi.org/10.1089/scd.2008.0117 CrossRefPubMedPubMedCentral

49.

Pierantozzi E, Badin M, Vezzani B et al (2015) Human pericytes isolated from adipose tissue have better differentiation abilities than their mesenchymal stem cell counterparts. Cell Tissue Res 361(3):769–778. https://doi.org/10.1007/s00441-015-2166-z CrossRefPubMed

50.

Dellavalle A, Maroli G, Covarello D et al (2011) Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat Commun 2. https://doi.org/10.1038/ncomms1508

51.

Crisan M, Corselli M, Chen WC, Peault B (2012) Perivascular cells for regenerative medicine. J Cell Mol Med 16(12):2851–2860. https://doi.org/10.1111/j.1582-4934.2012.01617.x CrossRefPubMedPubMedCentral

52.

Chen CW, Okada M, Proto JD et al (2013) Human pericytes for ischemic heart repair. Stem Cells 31(2):305–316. https://doi.org/10.1002/stem.1285 CrossRefPubMedPubMedCentral

53.

Campagnolo P, Cesselli D, Al Haj Zen A et al (2010) Human adult vena saphena contains perivascular progenitor cells endowed with clonogenic and proangiogenic potential. Circulation 121(15):1735–1745. https://doi.org/10.1161/CIRCULATIONAHA.109.899252 CrossRefPubMedPubMedCentral

54.

Katare R, Riu F, Mitchell K et al (2011) Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ Res 109(8):894–906. https://doi.org/10.1161/CIRCRESAHA.111.251546 CrossRefPubMedPubMedCentral

55.

Avolio E, Meloni M, Spencer HL et al (2015) Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair. Circ Res 116(10):e81–e94. https://doi.org/10.1161/CIRCRESAHA.115.306146 CrossRefPubMed

56.

Ferland-McCollough D, Slater S, Richard J, Reni C, Mangialardi G (2017) Pericytes, an overlooked player in vascular pathobiology. Pharmacol Ther 171:30–42. https://doi.org/10.1016/j.pharmthera.2016.11.008 CrossRefPubMedPubMedCentral

57.

O’Farrell FM, Attwell D (2014) A role for pericytes in coronary no-reflow. Nat Rev Cardiol 11(7):427–432. https://doi.org/10.1038/nrcardio.2014.58 CrossRefPubMed

58.

Dar A, Domev H, Ben-Yosef O A et al (2014) Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation 2012; 125(1): 87–99. https://doi.org/10.1161/CIRCULATIONAHA.111.048264 CrossRef

59.

Kobayashi K, Sato K, Kida T et al (2014) Stromal cell-derived factor-1alpha/C-X-C chemokine receptor type 4 axis promotes endothelial cell barrier integrity via phosphoinositide 3-kinase and Rac1 activation. Arterioscler Thromb Vasc Biol 34(8):1716–1722. https://doi.org/10.1161/ATVBAHA.114.303890 CrossRefPubMed

60.

DiPersio JF (2011) Diabetic stem-cell mobilopathy. N Engl J Med 365(26):2536–2538. https://doi.org/10.1056/NEJMcibr1112347 CrossRefPubMed

61.

Papetti M, Shujath J, Riley KN, Herman IM (2003) FGF-2 antagonizes the TGF-beta1-mediated induction of pericyte alpha-smooth muscle actin expression: a role for myf-5 and Smad-mediated signaling pathways. Invest Ophthalmol Vis Sci 44(11):4994–5005. https://doi.org/10.1167/iovs.03-0291 CrossRefPubMed

62.

Yeoh JSG, van Os R, Weersing E et al (2006) Fibroblast growth factor-1 and-2 preserve long-term repopulating ability of hematopoietic stem cells in serum-free cultures. Stem Cells 24(6):1564–1572. https://doi.org/10.1634/stemcells.2005-0439 CrossRefPubMed

63.

Arai F, Hirao A, Ohmura M et al (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118(2):149–161. https://doi.org/10.1016/j.cell.2004.07.004 CrossRefPubMed

64.

Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nature reviews. Mol Cell Biol 10(3):165–177. https://doi.org/10.1038/nrm2639 CrossRef

65.

Daly C, Wong V, Burova E et al (2004) Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 18(9):1060–1071. https://doi.org/10.1101/gad.1189704 CrossRefPubMedPubMedCentral

66.

Yuan HT, Khankin EV, Karumanchi SA, Parikh SM (2009) Angiopoietin 2 Is a Partial Agonist/Antagonist of Tie2 Signaling in the Endothelium. Mol Cell Biol 29(8):2011–2022. https://doi.org/10.1128/Mcb.01472-08 CrossRefPubMedPubMedCentral

67.

Teichert M, Milde L, Holm A, Stanicek L, Gengenbacher N, Savant S et al (2017) Pericyte expressed Tie2 controls angiogenesis and vessel maturation. Nat Commun 8:16106. https://doi.org/10.1038/ncomms16106 CrossRefPubMedPubMedCentral

Title: Bone marrow pericyte dysfunction in individuals with type 2 diabetes
Authors: Giuseppe Mangialardi
David Ferland-McCollough
Davide Maselli
Marianna Santopaolo
Andrea Cordaro
Gaia Spinetti
Maria Sambataro
Niall Sullivan
Ashley Blom
Paolo Madeddu
Publication date: 01-07-2019
Publisher: Springer Berlin Heidelberg
Keyword: Type 2 Diabetes
Published in: Diabetologia / Issue 7/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4865-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 7/2019

Continuous glucose monitoring targets in type 1 diabetes pregnancy: every 5% time in range matters

ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice

Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice

Genome-wide association study of type 2 diabetes in Africa

Human gut microbiota transferred to germ-free NOD mice modulate the progression towards type 1 diabetes regardless of the pace of beta cell function loss in the donor

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials