When Good Guys Turn Bad: Bone Marrow’s and Hematopoietic Stem Cells’ Role in the Pathobiology of Diabetic Complications

Vinci, Maria; Gambini, Elisa; Bassetti, Beatrice; Genovese, Stefano; Pompilio, Giulio

doi:10.3390/ijms21113864

Cited by 19 publications

(18 citation statements)

References 183 publications

(213 reference statements)

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“…To this regard, a chronic low-grade inflammation and immune activation have been described both in pre-diabetic and diabetic states [ 27 , 28 , 29 , 30 ]. A consisting body of literature suggests that the impact of hyperglycemia on HSPCs in the BM niche may be the primary factor contributing to CV disease development [ 31 , 32 ]. Indeed, numerous preclinical data show the ability of BM diabetic environment to boost HSPC differentiation toward myeloid lineage as well as to promote abnormal generation and accumulation of immune cell subpopulations (e.g., monocytes and macrophages) with more aggressive phenotypes [ 33 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

D’Alessandra

Chiesa

Vigorelli

et al. 2021

IJMS

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Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34+ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.

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Section: Discussionmentioning

confidence: 99%

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

D’Alessandra

Chiesa

Vigorelli

et al. 2021

IJMS

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“…Recently, delayed fracture healing due to the BMP6 downregulation has been reported in a streptozotocin-induced rat diabetes model ( 43 ). The low Bmp6 expression levels in smooth muscle progenitor cells in a mouse diabetes model ( 44 ) and in myofibroblast progenitor cells of patients with diabetes ( 45 ) has suggested the role of BMP6 in vascular tissue remodeling, which may promote the generation of cells with antiangiogenic and profibrotic properties ( 46 ). The present study aimed to investigate whether exocrine pancreatic damage may impact glucose metabolism in aging Bmp6 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Iron overload in aging Bmp6^‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss

et al. 2021

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The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6-knockout ( Bmp6 −/− ) mouse model of hemochromatosis. The sera and pancreatic tissues of wild-type (WT) and Bmp6 −/− mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, 18 F-fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3-month-old Bmp6 −/− mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging Bmp6 −/− mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α-cell mass compared with those in the age-matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging Bmp6 −/− mice leading to iron-induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.

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“…Diabetes leads to numerous abnormalities in the BM, such as small vessel disease (microangiopathy), nerve terminal damage (neuropathy), and impaired stem cell mobilization (mobilopathy) [87]. These pathologic manifestations are elicited by a dramatic shift in the local BM microenvironment, which includes changes to the inflammatory milieu and the cellular components of the niche (reviewed in [88]). Diabetes results in systemic dysfunction of endothelial cells [89], and there is diminished mobilization of endothelial progenitor cells (EPCs) from the BM into the blood in diabetes [90].…”

Section: Diabetes-mediated Changes To the Bone Marrow Nichementioning

confidence: 99%

Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease

Murphy

Fleetwood

2022

IJMS

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It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of “memory” in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease.

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When Good Guys Turn Bad: Bone Marrow’s and Hematopoietic Stem Cells’ Role in the Pathobiology of Diabetic Complications

Cited by 19 publications

References 183 publications

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

Iron overload in aging Bmp6^‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss

Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease

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When Good Guys Turn Bad: Bone Marrow’s and Hematopoietic Stem Cells’ Role in the Pathobiology of Diabetic Complications

Cited by 19 publications

References 183 publications

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

Diabetes Induces a Transcriptional Signature in Bone Marrow–Derived CD34+ Hematopoietic Stem Cells Predictive of Their Progeny Dysfunction

Iron overload in aging Bmp6‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss

Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease

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Iron overload in aging Bmp6^‑/‑ mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss