Research

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15 pages, 3865 KiB

Open AccessArticle

Attenuation of Flightless I Increases Human Pericyte Proliferation, Migration and Angiogenic Functions and Improves Healing in Murine Diabetic Wounds

by Hannah M Thomas, Parinaz Ahangar, Benjamin R Hofma, Xanthe L Strudwick, Robert Fitridge, Stuart J Mills and Allison J Cowin

Int. J. Mol. Sci. 2020, 21(16), 5599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165599 - 05 Aug 2020

Cited by 12 | Viewed by 2503

Abstract

Pericytes are peri-vascular mural cells which have an important role in the homeostatic regulation of inflammatory and angiogenic processes. Flightless I (Flii) is a cytoskeletal protein involved in regulating cellular functions, but its involvement in pericyte activities during wound healing is unknown. Exacerbated [...] Read more.

Pericytes are peri-vascular mural cells which have an important role in the homeostatic regulation of inflammatory and angiogenic processes. Flightless I (Flii) is a cytoskeletal protein involved in regulating cellular functions, but its involvement in pericyte activities during wound healing is unknown. Exacerbated inflammation and reduced angiogenesis are hallmarks of impaired diabetic healing responses, and strategies aimed at regulating these processes are vital for improving healing outcomes. To determine the effect of altering Flii expression on pericyte function, in vitro and in vivo studies were performed to assess the effect on healing, inflammation and angiogenesis in diabetic wounds. Here, we demonstrated that human diabetic wounds display upregulated expression of the Flii protein in conjunction with a depletion in the number of platelet derived growth factor receptor β (PDGFRβ) +/ neural glial antigen 2 (NG2) + pericytes present in the dermis. Human pericytes were found to be positive for Flii and attenuating its expression in vitro through siRNA knockdown led to enhanced proliferation, migration and angiogenic functions. Genetic knockdown of Flii in a streptozotocin-induced murine model of diabetes led to increased numbers of pericytes within the wound. This was associated with dampened inflammation, an increased rate of angiogenic repair and improved wound healing. Our findings show that Flii expression directly impacts pericyte functions, including proliferation, motility and angiogenic responses. This suggests that Flii regulation of pericyte function may be in part responsible for the changes in pericyte-related processes observed in diabetic wounds. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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16 pages, 5130 KiB

Open AccessArticle

Evaluation of the In Vitro Damage Caused by Lipid Factors on Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence

by Istvan Kovanecz, Robert Gelfand, Sheila Sharifzad, Alec Ohanian, William Brent DeCastro, Carley Cooper, Guiting Lin, Tom Lue and Nestor F. Gonzalez-Cadavid

Int. J. Mol. Sci. 2020, 21(14), 5045; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145045 - 17 Jul 2020

Cited by 1 | Viewed by 2226

Abstract

Human stem cell therapy for type 2 diabetes/obesity (T2D/O) complications is performed
with stem cell autografts, exposed to the noxious T2D/O milieu, often with suboptimal results.
We showed in the Obese Zucker (OZ) rat model of T2D/O that when their muscle-derived stem
cells [...] Read more.

Human stem cell therapy for type 2 diabetes/obesity (T2D/O) complications is performed
with stem cell autografts, exposed to the noxious T2D/O milieu, often with suboptimal results.
We showed in the Obese Zucker (OZ) rat model of T2D/O that when their muscle-derived stem
cells (MDSC) were from long-term T2D/O male rats, their repair ecacy for erectile dysfunction
was impaired and were imprinted with abnormal gene- and miR-global transcriptional signatures
(GTS). The damage was reproduced in vitro by short-term exposure of normal MDSC to dyslipidemic
serum, causing altered miR-GTS, fat infiltration, apoptosis, impaired scratch healing, and myostatin
overexpression. Similar in vitro alterations occurred with their normal counterparts (ZF4-SC) from
the T2D/O rat model for female stress urinary incontinence, and with ZL4-SC from non-T2D/O lean
female rats. In the current work we studied the in vitro eects of cholesterol and Na palmitate as
lipid factors on ZF4-SC and ZL4-SC. A damage partially resembling the one caused by the female
dyslipidemic serum was found, but diering between both lipid factors, so that each one appears to
contribute specifically to the stem cell damaging eects of dyslipidemic serum in vitro and T2D/O
in vivo, irrespective of gender. These results also confirm the miR-GTS biomarker value for
MDSC damage. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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20 pages, 2588 KiB

Open AccessArticle

Impact of Type 2 Diabetes Mellitus on Human Bone Marrow Stromal Cell Number and Phenotypic Characteristics

by Féaron C. Cassidy, Ciara Shortiss, Colin G. Murphy, Stephen R. Kearns, William Curtin, Ciara De Buitléir, Timothy O’Brien and Cynthia M. Coleman

Int. J. Mol. Sci. 2020, 21(7), 2476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072476 - 02 Apr 2020

Cited by 31 | Viewed by 3568

Abstract

Human bone marrow-derived mesenchymal stromal cells (MSCs) have been investigated in numerous disease settings involving impaired regeneration because of the crucial role they play in tissue maintenance and repair. Considering the number of comorbidities associated with type 2 diabetes mellitus (T2DM), the hypothesis [...] Read more.

Human bone marrow-derived mesenchymal stromal cells (MSCs) have been investigated in numerous disease settings involving impaired regeneration because of the crucial role they play in tissue maintenance and repair. Considering the number of comorbidities associated with type 2 diabetes mellitus (T2DM), the hypothesis that MSCs mediate these comorbidities via a reduction in their native maintenance and repair activities is an intriguing line of inquiry. Here, it is demonstrated that the number of bone marrow-derived MSCs in people with T2DM was reduced compared to that of age-matched control (AMC) donors and that this was due to a specific decrease in the number of MSCs with osteogenic capacity. There were no differences in MSC cell surface phenotype or in MSC expansion, differentiation, or angiogenic or migratory capacity from donors living with T2DM as compared to AMCs. These findings elucidate the basic biology of MSCs and their potential as mediators of diabetic comorbidities, especially osteopathies, and provide insight into donor choice for MSC-based clinical trials. This study suggests that any role of bone marrow MSCs as a mediator of T2DM comorbidity is likely due to a reduction in the osteoprogenitor population size and not due to a permanent alteration to the MSCs’ capacity to maintain tissue homeostasis through expansion and differentiation. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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20 pages, 4504 KiB

Open AccessArticle

Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence Are Damaged by In Vitro Exposure to its Dyslipidemic Serum, Predicting Inadequate Repair Capacity In Vivo

by Istvan Kovanecz, Robert Gelfand, Guiting Lin, Sheila Sharifzad, Alec Ohanian, Randy Ricks, Tom Lue and Nestor F. Gonzalez-Cadavid

Int. J. Mol. Sci. 2019, 20(16), 4044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20164044 - 19 Aug 2019

Cited by 5 | Viewed by 3268

Abstract

Female stress urinary incontinence (FSUI) is prevalent in women with type 2 diabetes/obesity (T2D/O), and treatment is not optimal. Autograph stem cell therapy surprisingly has poor efficacy. In the male rat model of T2D/O, it was demonstrated that epigenetic changes, triggered by long-term [...] Read more.

Female stress urinary incontinence (FSUI) is prevalent in women with type 2 diabetes/obesity (T2D/O), and treatment is not optimal. Autograph stem cell therapy surprisingly has poor efficacy. In the male rat model of T2D/O, it was demonstrated that epigenetic changes, triggered by long-term exposure to the dyslipidemic milieu, led to abnormal global transcriptional signatures (GTS) of genes and microRNAs (miR), and impaired the repair capacity of muscle-derived stem cells (MDSC). This was mimicked in vitro by treatment of MDSC with dyslipidemic serum or lipid factors. The current study aimed to predict whether these changes also occur in stem cells from female 12 weeks old T2D/O rats, a model of FSUI. MDSCs from T2D/O (ZF4-SC) and normal female rats (ZL4-SC) were treated in vitro with either dyslipidemic serum (ZFS) from late T2D/O 24 weeks old female Zucker fatty (ZF) rats, or normal serum (ZLS) from 24 weeks old female Zucker lean (ZL) rats, for 4 days and subjected to assays for fat deposition, apoptosis, scratch closing, myostatin, interleukin-6, and miR-GTS. The dyslipidemic ZFS affected both female stem cells more severely than in the male MDSC, with some gender-specific differences in miR-GTS. The changes in miR-GTS and myostatin/interleukin-6 balance may predict in vivo noxious effects of the T2D/O milieu that might impair autograft stem cell (SC) therapy for FSUI, but this requires future studies. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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Review

Jump to: Research

22 pages, 1718 KiB

Open AccessReview

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

by Maria Cristina Vinci, Elisa Gambini, Beatrice Bassetti, Stefano Genovese and Giulio Pompilio

Int. J. Mol. Sci. 2020, 21(11), 3864; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113864 - 29 May 2020

Cited by 15 | Viewed by 3727

Abstract

Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, [...] Read more.

Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, a recent study demonstrated that type 2 diabetic patients are characterized by significant depletion of circulating provascular progenitor cells and increased frequency of inflammatory cells. This unbalance, potentially responsible for the reduction of intrinsic vascular homeostatic capacity and for the establishment of a low-grade inflammatory status, suggests that bone BM-derived HSPCs are not only victims but also active perpetrators in diabetic complications. In this review, we will discuss the most recent literature on the molecular mechanisms underpinning hyperglycemia-mediated BM dysfunction and differentiation abnormality of HSPCs. Moreover, a section will be dedicated to the new glucose-lowering therapies that by specifically targeting the culprits may prevent or treat diabetic complications. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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20 pages, 1858 KiB

Open AccessReview

Novel Cell-Based and Tissue Engineering Approaches for Induction of Angiogenesis as an Alternative Therapy for Diabetic Retinopathy

by Elmira Jalilian, Kenneth Elkin and Su Ryon Shin

Int. J. Mol. Sci. 2020, 21(10), 3496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103496 - 15 May 2020

Cited by 9 | Viewed by 7626

Abstract

Diabetic retinopathy (DR) is the most frequent microvascular complication of long-term diabetes and the most common cause of blindness, increasing morbidity in the working-age population. The most effective therapies for these complications include laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections. [...] Read more.

Diabetic retinopathy (DR) is the most frequent microvascular complication of long-term diabetes and the most common cause of blindness, increasing morbidity in the working-age population. The most effective therapies for these complications include laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections. However, laser and anti-VEGF drugs are untenable as a final solution as they fail to address the underlying neurovascular degeneration and ischemia. Regenerative medicine may be a more promising approach, aimed at the repair of blood vessels and reversal of retinal ischemia. Stem cell therapy has introduced a novel way to reverse the underlying ischemia present in microvascular complications in diseases such as diabetes. The present review discusses current treatments, their side effects, and novel cell-based and tissue engineering approaches as a potential alternative therapeutic approach. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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11 pages, 690 KiB

Open AccessReview

Adult Stem Cell Therapeutics in Diabetic Retinopathy

by Sriprachodaya Gaddam, Ramesh Periasamy and Rajashekhar Gangaraju

Int. J. Mol. Sci. 2019, 20(19), 4876; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194876 - 30 Sep 2019

Cited by 36 | Viewed by 6033

Abstract

Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell [...] Read more.

Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell therapeutics, have shown variable efficacy in preclinical models due to the multi-faceted nature of the disease. Among the various adult stem cells, mesenchymal stem cells, especially those derived from adipose tissue and bone marrow, have been explored as a possible treatment for DR. This review summarizes the current literature around the various adult stem cell treatments for the disease and outlines the benefits and limitations of the therapeutics that are being explored in the field. The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue. Various methods of mesenchymal stem cell priming to adapt to a hostile retinal microenvironment have been discussed. Current clinical trials and potential safety concerns have been examined, and the future directions of stem cell therapeutics in DR have also been contemplated. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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23 pages, 1231 KiB

Open AccessReview

Impact of Diabetes Mellitus on Bone Health

by Cliodhna E. Murray and Cynthia M. Coleman

Int. J. Mol. Sci. 2019, 20(19), 4873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194873 - 30 Sep 2019

Cited by 118 | Viewed by 11734

Abstract

Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical [...] Read more.

Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field. Full article

(This article belongs to the Special Issue Bone Marrow and Stem Cell Alterations in Diabetes: Causes, Consequences and Therapeutics)

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