Bone marrow pericyte dysfunction in individuals with type 2 diabetes.

Authors:
Giuseppe Mangialardi
Giuseppe Mangialardi
Bristol Heart Institute
Davide Maselli
Davide Maselli
University Hospital of Parma
Marianna Santopaolo
Marianna Santopaolo
Università degli Studi di Napoli "Federico II" Napoli
Napoli | Italy
Gaia Spinetti
Gaia Spinetti
University of Bristol
United Kingdom
Maria Sambataro
Maria Sambataro
Metabolism Disease and Clinical Nutrition Unit
Niall Sullivan
Niall Sullivan
Southmead Hospital
United Kingdom

Diabetologia 2019 Apr 17. Epub 2019 Apr 17.

Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol, BS2 8HW, UK.

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.

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Source
http://link.springer.com/10.1007/s00125-019-4865-6
Publisher Site
http://dx.doi.org/10.1007/s00125-019-4865-6DOI Listing
April 2019
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