Mangialardi, G., & Madeddu, P. (2016). Bone Marrow-Derived Stem Cells: A Mixed Blessing in the Multifaceted World of Diabetic Complications. Current diabetes reports, 16(5), [43]. https://doi.org/10.1007/s11892-016-0730-x Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1007/s11892-016-0730-x Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Current Medicine Group at http://dx.doi.org/ 10.1007/s11892-016-0730-x. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Curr Diab Rep (2016) 16: 43 DOI 10.1007/s11892-016-0730-x IMMUNOLOGY AND TRANSPLANTATION (L PIEMONTI AND V SORDI, SECTION EDITORS) Bone Marrow-Derived Stem Cells: a Mixed Blessing in the Multifaceted World of Diabetic Complications Giuseppe Mangialardi1 & Paolo Madeddu1 Published online: 30 March 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Diabetes is one of the main economic burdens in Introduction health care, which threatens to worsen dramatically if preva- lence forecasts are correct. What makes diabetes harmful is the Diabetes mellitus (DM) is a family of metabolic disorders multi-organ distribution of its microvascular and characterized by high blood glucose levels. Worldwide, there macrovascular complications. Regenerative medicine with are about 387 million people affected by DM, with a preva- cellular therapy could be the dam against life-threatening or lence in North America of 11.4 % (39 million) and in Europe life-altering complications. Bone marrow-derived stem cells of 7.9 % (52 million) (http://www.idf.org/sites/default/files/ are putative candidates to achieve this goal. Unfortunately, the DA-regional-factsheets-2014_FINAL.pdf). Estimation for bone marrow itself is affected by diabetes, as it can develop a 2035 foresees 592 million patients with diabetes on the microangiopathy and neuropathy similar to other body tissues. planet. It is not surprising that DM is one of the heaviest Neuropathy leads to impaired stem cell mobilization from economic health burdens, with an annual global cost of 548 marrow, the so-called mobilopathy. Here, we review the role million USD raising to 627 million in 2035 (http://www.idf. of bone marrow-derived stem cells in diabetes: how they are org/sites/default/files/DA-regional-factsheets-2014_FINAL. affected by compromised bone marrow integrity, how they pdf). contribute to other diabetic complications, and how they can There are several types of DM. Type 1 diabetes be used as a treatment for these. Eventually, we suggest new (T1DM) is an autoimmune disease characterized by β- tactics to optimize stem cell therapy. cell destruction in the pancreatic islets resulting in the complete loss of insulin secretion. Type 2 diabetes (T2DM), the prevalent form of DM, is a multifactorial Keywords Diabetes . Diabetic complications . Bone disease characterized by insulin resistance. Gestational di- marrow . Stem cells . Microangiopathy . Cell regenerative abetes (GDM) occurs in pregnant women without previous therapy history of DM. Chronic hyperglycemia causes systemic complications, with cardiovascular complications being particularly frequent and worrisome [1]. Diabetic macrovascular disease manifests as coronary artery disease This article is part of the Topical Collection on Immunology and (CAD), myocardial infarction (MI), peripheral artery dis- Transplantation ease (PAD), and stroke. Microvascular disease results from damage to the small vessels and can aggravate the out- * Paolo Madeddu come of patients with occlusive macrovascular disease. [email protected] Compared to hospital costs of people without complica- Giuseppe Mangialardi tions, hospital costs of those with microvascular complica- [email protected] tions are doubled, those of people with macrovascular complications are tripled, and those of people with both 1 Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal micro- and macrovascular complications are six times as Infirmary, Upper Maudlin Street, Bristol BS28HW, UK great. Lifestyle interventions, such as changes in diet and 43 Page 2 of 12 Curr Diab Rep (2016) 16: 43 exercise, and medications are essential in reducing the risk Hematopoietic Stem Cells for development of complications. Thanks to improved management, the prevalence of diabetic complications is Hematopoietic stem cells (HSCs) constitute a very heteroge- constantly decreasing, but these improved clinical out- neous population, which can give rise to any blood cell. They comes came with a cost of £708 million per year in the are defined as proper stem cells because of their self-renewal UK, corresponding to 7 % of the UK health-care prescrib- capacity and multipotency [4]. BM transplantation assays in ing budget [2]. Nevertheless, once cardiovascular compli- animal models helped to establish a possible hierarchical cations occur, these are more difficult to treat in patients structure. Accordingly, based on repopulating capacity upon with DM as compared with patients without DM. This transplantation into irradiated animals, two different popula- difference has been explained with the fact that healing tions have been identified and defined as short-term HSCs and regenerative mechanisms are remarkably altered in (ST-HSC) and long-term HSCs (LT-HSCs) [5]. In humans, patients with DM. the surface marker CD34, a member of a family of single- The current care of cardiovascular complications com- pass transmembrane glycoproteins, is considered the main prises pharmacotherapy and revascularization. However, defining marker for HSCs and the marker of choice to select medical treatment can be ineffective as in the case of refrac- populations for clinical cell therapy trials. Depleting CD34+ tory angina, which is prevalent in patients with DM. cells for Lin antigen enables their enrichment into a more Additionally, in many patients with DM, revascularization primitive population with hematopoietic function. Further en- cannot be applied due to multiple and distal occlusions, or it richment could be achieved by selecting the latter population fails because of restenosis. But the most important limitation for Thy1, a primitive stem cell marker, and depleting for of medical and interventional treatments is that, even when CD38 and CD45RA markers (multipotent progenitors), with successful, they do not replace cells irreversibly damaged by additional positivity for CD49f defining proper LT-HSCs [6]. ischemia. Therefore, intense research is focused on regenera- In the mouse, LT-HSCs are identified as CD34−/c-Kit+/Sca- tive medicine as a novel option for the treatment of cardiovas- 1+/Lineage− (CD34−/KSL) cells. However, CD34−/KSL cular complications. This approach consists of augmenting cells represent a heterogeneous population containing sub- endogenous mechanisms of repair by supplements of regen- fractions with diverse regenerative capacity. Further character- erative cells, for instance through transplantation of stem cells/ ization by use of the signaling lymphocyte activation mole- progenitor cells into the infarcted myocardium. Alternatively, cule (SLAM) markers CD48 and CD150 allows the identifi- cytokines and growth factors could be delivered to boost the cation of a fraction of CD34−/KSL cells endowed with high liberation of progenitor cells from the bone marrow (BM) or self-renewal potential and repopulating capacity [4]. The sem- the expansion of resident progenitor cells in the heart and inal concept of BM HSCs directly participating in de novo other ischemic tissues. To date, a few thousand individuals post-natal vasculogenesis, proposed some years ago by worldwide have received stem cells—mainly BM cells—in Asahara et al. [7], has been revised in light of the novel indi- cardiovascular clinical trials [3]. cation that paracrine mechanisms, rather than the conversion In this review, we provide a concise report of the latest of one cell type to another, control the interrelation between findings about cell therapy for treatment of diabetic complica- hematopoietic and vascular cells [8]. tions, with particular focus on approaches based on BM- derived cells. We also discuss the pros and cons of BM cell Mesenchymal Stem Cells therapy, especially in light of new discoveries that common complications of DM, namely microangiopathy and neuropa- Mesenchymal stem cells (MSCs) are a heterogeneous thy, affect also the BM and may jeopardize stem cell mobili- multipotent stromal cell population well represented in BM zation following an ischemic event or stimulation by cyto- as well as in several other adult tissues. They are defined as kines. Finally, we propose some possible solutions to improve plastic-adherent, fibroblast-like cells endowed with high pro- current cell therapy approaches. liferative activity and capacity to differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells) [9]. They typically express the mesenchymal markers Bone Marrow-Derived Stem