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Progenitor Cell Dysfunctions Underlie Some Diabetic Complications

2015; Elsevier BV; Volume: 185; Issue: 10 Linguagem: Inglês

10.1016/j.ajpath.2015.05.003

ISSN

1525-2191

Autores

Mélanie Rodrigues, Victor W. Wong, Robert C. Rennert, Christopher R. Davis, Michael T. Longaker, Geoffrey C. Gurtner,

Tópico(s)

Metabolism, Diabetes, and Cancer

Resumo

Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications. Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications. Diabetes is characterized by insulin resistance and hyperglycemia, and affects a diverse array of cells, leading to a myriad of tissue complications. These include, but are not limited to, cardiac arrest, stroke, nephropathy, retinopathy, and non-traumatic lower limb amputations.1Centers for Disease Control and PreventionNational diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. 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True stem cells exhibit both these criteria, whereas progenitor cells or transit amplifying cells cannot self-renew in perpetuity. In the adult tissue, hematopoietic stem cells (HSCs) are the only cells known to repopulate the hematopoietic system, making them indispensable for repair and regeneration.16Seita J. Weissman I.L. Hematopoietic stem cell: self-renewal versus differentiation.Wiley Interdiscip Rev Syst Biol Med. 2010; 2: 640-653Crossref PubMed Scopus (92) Google Scholar, 17Oguro H. Ding L. Morrison S.J. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors.Cell Stem Cell. 2013; 13: 102-116Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar HSCs reside in the bone marrow, harbored by mesenchymal stromal cells (MSCs) with multipotent differentiation capacity.18Pittenger M.F. Mackay A.M. Beck S.C. Jaiswal R.K. Douglas R. Mosca J.D. Moorman M.A. Simonetti D.W. Craig S. Marshak D.R. 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Tsai C.R. Goodell M.A. Rando T.A. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert).Nature. 2014; 510: 393-396PubMed Google Scholar Imbalance within these states can have pathological consequences on the body's ability to repair injured tissues.36Rossi L. Lin K.K. Boles N.C. Yang L. King K.Y. Jeong M. Mayle A. Goodell M.A. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice.Cell Stem Cell. 2012; 11: 302-317Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 37Beerman I. Seita J. Inlay M.A. Weissman I.L. Rossi D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle.Cell Stem Cell. 2014; 15: 37-50Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 38Malam Z. Cohn R.D. 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Complete consumption of substrates, including glucose, that occur during oxidative phosphorylation may be insufficient to support the energy requirements of the stem cell. Instead, stem cells are postulated to prefer glycolysis, which allows for partial breakdown of glucose and shunting of intermediates through the pentose phosphate pathway. This allows for both the catabolic process of ATP generation and the production of substrates for anabolic processes.40Folmes C.D. Dzeja P.P. Nelson T.J. Terzic A. Metabolic plasticity in stem cell homeostasis and differentiation.Cell Stem Cell. 2012; 11: 596-606Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 41Folmes C.D. Nelson T.J. Martinez-Fernandez A. Arrell D.K. Lindor J.Z. Dzeja P.P. Ikeda Y. Perez-Terzic C. Terzic A. 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Other nutrient- and glucose-sensing mechanisms detailing the exit from quiescence and the activation of stem cells are being actively investigated. Induction of autophagy, the process of self-eating of cellular components, is emerging as one of the alternate mechanisms by which stem cells rapidly meet their bioenergetics demands and get activated. This mode of activation has been studied in embryonic stem cells, HSCs, MSCs, and neural stem cells (NSCs).44Tang A.H. Rando T.A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation.EMBO J. 2014; 33: 2782-2797Crossref PubMed Scopus (10) Google Scholar, 45Nuschke A. Rodrigues M. Stolz D.B. Chu C.T. Griffith L. Wells A. Human mesenchymal stem cells/multipotential stromal cells consume accumulated autophagosomes early in differentiation.Stem Cell Res Ther. 2014; 5: 140Crossref PubMed Google Scholar, 46Wang C. Liang C.C. Bian Z.C. Zhu Y. Guan J.L. FIP200 is required for maintenance and differentiation of postnatal neural stem cells.Nat Neurosci. 2013; 16: 532-542Crossref PubMed Scopus (5) Google Scholar Correlative studies demonstrate that aging and diabetes perturb and inhibit the autophagic machinery of cells.47Rubinsztein D.C. Marino G. Kroemer G. Autophagy and aging.Cell. 2011; 146: 682-695Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar, 48Yang L. Li P. Fu S. Calay E.S. Hotamisligil G.S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.Cell Metab. 2010; 11: 467-478Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar This would suggest that a specific disruption of the autophagic signaling in stem cells in response to the diabetic state might contribute to the dysfunctional stem cell phenotype. Diabetes is associated with a myriad of tissue-specific complications. These include, but are not limited to, renal failure, blindness, neuropathy, atherosclerosis, and cardiac failure. Diabetes also results in generic complications, such as impaired neovascularization and microvascular complications, resulting in ulcers and chronic nonhealing wounds. There is increasing evidence that suggests that stem cell dysfunction underlies some of these complications. Exposure to hyperglycemia is found to produce both stem cell deficits and alterations in the tissue microenvironment surrounding the stem cell.49Ceradini D.J. Gurtner G.C. Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue.Trends Cardiovasc Med. 2005; 15: 57-63Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 50Thangarajah H. Vial I.N. Grogan R.H. Yao D. Shi Y. Januszyk M. Galiano R.D. Chang E.I. Galvez M.G. Glotzbach J.P. Wong V.W. Brownlee M. Gurtner G.C. 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Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia.Am J Pathol. 2003; 162: 303-312Abstract Full Text Full Text PDF PubMed Google Scholar These impairments include, but are not limited to, changes in migration, recruitment, survival, self-renewal, and differentiation capacity (Figure 1). This section details the changes produced by hyperglycemia in stem cells of the bone marrow, nervous system, bone, and heart. Diabetes produces a global remodeling of the bone marrow. From a stem cell standpoint, there is decreased efflux of diabetic progenitors from the marrow and reduced vasculogenic potential of these cells.54Fadini G.P. Albiero M. Vigili de Kreutzenberg S. Boscaro E. Cappellari R. Marescotti M. Poncina N. Agostini C. Avogaro A. Diabetes impairs stem cell and proangiogenic cell mobilization in humans.Diabetes Care. 2013; 36: 943-949Crossref PubMed Scopus (38) Google Scholar Murine models of both type 1 and type 2 diabetes confirm this impaired egress of bone marrow progenitors after injury.13Ferraro F. Lymperi S. Mendez-Ferrer S. Saez B. Spencer J.A. Yeap B.Y. Masselli E. Graiani G. Prezioso L. Rizzini E.L. Mangoni M. Rizzoli V. Sykes S.M. Lin C.P. Frenette P.S. Quaini F. Scadden D.T. Diabetes impairs hematopoietic stem cell mobilization by altering niche function.Sci Transl Med. 2011; 3: 104ra1Crossref Scopus (33) Google Scholar, 55Januszyk M. Sorkin M. Glotzbach J.P. Vial I.N. Maan Z.N. Rennert R.C. Duscher D. Thangarajah H. Longaker M.T. Butte A.J. Gurtner G.C. Diabetes irreversibly depletes bone marrow-derived mesenchymal progenitor cell subpopulations.Diabetes. 2014; 63: 3047-3056Crossref PubMed Scopus (3) Google Scholar Furthermore, clinical studies demonstrate that diabetes causes a reduction of hematopoietic tissue, increased fat deposition, and microvascular rarefaction in the bone marrow.56Spinetti G. Cordella D. Fortunato O. Sangalli E. Losa S. Gotti A. Carnelli F. Rosa F. Riboldi S. Sessa F. Avolio E. Beltrami A.P. Emanueli C. Madeddu P. Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway.Circ Res. 2013; 112: 510-522Crossref PubMed Scopus (31) Google Scholar These changes have a cumulative negative outcome on progenitor cells. More important, diabetic patients with satisfactory glycemic control display more circulatory progenitors than patients with poor glycemic control, but fewer progenitors compared with nondiabetics.57Yue W.S. Lau K.K. Siu C.W. Wang M. Yan G.H. Yiu K.H. Tse H.F. Impact of glycemic control on circulating endothelial progenitor cells and arterial stiffness in patients with type 2 diabetes mellitus.Cardiovasc Diabetol. 2011; 10: 113Crossref PubMed Scopus (29) Google Scholar This suggests that normalizing glucose levels after hyperglycemia may not be sufficient to normalize tissue homeostasis. The effect of diabetes on stem cells is not limited to the adult tissue alone. Maternal diabetes produces a hyperglycemic environment for the developing embryo and has been linked to congenital malformations in various tissues, including the nervous system. NSCs are self-renewing multipotent cells that produce neurons and glia (astrocytes and oligodendrocytes) of the central nervous system. Exposure of the fetus to high glucose has been found to impair NSCs in the developing brain, altering cell fate and producing neural tube defects. These include spina bifida, anencephaly, craniorachischisis, and encephalocele.58Zabihi S. Loeken M.R. Understanding diabetic teratogenesis: where are we now and where are we going?.Birth Defects Res A Clin Mol Teratol. 2010; 88: 779-790Crossref PubMed Google Scholar Specifically, exposure to high glucose produces epigenetic changes in NSCs: histone H3K9 trimethylation, DNA methylation, and decreased histone H3K9 acetylation. These changes alter genes, such as Dcx and Pafah1b1, which regulate neural migration and microtubule formation in the cortex. Neurogenesis and neural migration are affected by these changes.59Shyamasundar S. Jadhav S.P. Bay B.H. Tay S.S. Kumar S.D. Rangasamy D. Dheen S.T. Analysis of epigenetic factors in mouse embryonic neural stem cells exposed to hyperglycemia.PLoS One. 2013; 8: e65945Crossref PubMed Scopus (6) Google Scholar Hyperglycemia also induces reactive oxygen species (ROS) production and intracellular oxidative stress in NSCs, altering the balance between their proliferation and apoptosis.60Fu J. Tay S.S. Ling E.A. Dheen S.T. Aldose reductase is implicated in high glucose-induced oxidative stress in mouse embryonic neural stem cells.J Neurochem. 2007; 103: 1654-1665Crossref PubMed Scopus (9) Google Scholar Reduction of ROS is, therefore, one strategy to overcome NSC dysfunction during fetal development in the presence of high glucose. In the bone microenvironment, after injury, diabetes has been found to impair blood supply to the fracture site undermining bony union. Diabetes also leads to increased bone resorption and osteopenia, significantly increasing the risk of fractures.61Vestergaard P. Rejnmark L. Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk.Diabetologia. 2005; 48: 1292-1299Crossref PubMed Scopus (171) Google Scholar Increased reactive oxygen

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