PMID- 31001672 OWN - NLM STAT- MEDLINE DCOM- 20200316 LR - 20200316 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 62 IP - 7 DP - 2019 Jul TI - Bone marrow pericyte dysfunction in individuals with type 2 diabetes. PG - 1275-1290 LID - 10.1007/s00125-019-4865-6 [doi] AB - 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. FAU - Mangialardi, Giuseppe AU - Mangialardi G AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. FAU - Ferland-McCollough, David AU - Ferland-McCollough D AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. FAU - Maselli, Davide AU - Maselli D AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. AD - IRCCS Multimedica, Milan, Italy. AD - Department of Biochemistry, University of Sassari, Sassari, Italy. FAU - Santopaolo, Marianna AU - Santopaolo M AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. FAU - Cordaro, Andrea AU - Cordaro A AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. FAU - Spinetti, Gaia AU - Spinetti G AD - IRCCS Multimedica, Milan, Italy. FAU - Sambataro, Maria AU - Sambataro M AD - Department of Specialized Medicines, Endocrine, Metabolic and Nutrition Diseases Unit, Santa Maria of Ca' Foncello Hospital, Treviso, Italy. FAU - Sullivan, Niall AU - Sullivan N AD - Muscloskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. FAU - Blom, Ashley AU - Blom A AD - Muscloskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. FAU - Madeddu, Paolo AU - Madeddu P AD - Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK. mdprm@bristol.ac.uk. LA - eng GR - RG/13/17/30545/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190417 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 SB - IM EIN - Diabetologia. 2019 May 21;:. PMID: 31115642 MH - Adult MH - Aged MH - Aged, 80 and over MH - Bone Marrow Cells/*pathology MH - Diabetes Mellitus, Type 2/*pathology MH - Endothelial Cells/pathology MH - Female MH - Flow Cytometry MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Pericytes/*pathology MH - Signal Transduction/physiology PMC - PMC6560025 OTO - NOTNLM OT - Angiocrine factors OT - Bone marrow OT - Diabetes OT - Microangiopathy OT - Pericytes EDAT- 2019/04/20 06:00 MHDA- 2020/03/17 06:00 PMCR- 2019/04/17 CRDT- 2019/04/20 06:00 PHST- 2019/01/23 00:00 [received] PHST- 2019/03/04 00:00 [accepted] PHST- 2019/04/20 06:00 [pubmed] PHST- 2020/03/17 06:00 [medline] PHST- 2019/04/20 06:00 [entrez] PHST- 2019/04/17 00:00 [pmc-release] AID - 10.1007/s00125-019-4865-6 [pii] AID - 4865 [pii] AID - 10.1007/s00125-019-4865-6 [doi] PST - ppublish SO - Diabetologia. 2019 Jul;62(7):1275-1290. doi: 10.1007/s00125-019-4865-6. Epub 2019 Apr 17.