Functional Investigation of Endothelial Function and Regenerative Cell Exhaustion

NCT06108388 | Not Yet Recruiting

• 1 other identifier: Pro00074548
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

FIERCE is an observational cross-sectional study. Approximately 90 individuals living with type 2 diabetes (T2D) and/or individuals living without diabetes will be randomized (2:1). The primary objective of this trial is to determine if there are differences in the content and function of circulating vascular regenerative (VR) progenitor cell subsets isolated from individuals living with T2D versus individuals not living with T2D. The main question this study aims to answer is: Does T2D compromise or enhance VR cell functionality? Each participant will be asked to provide a single blood sample. Blood samples will be processed to enumerate the number of vessel-repairing cells and determine the functionality of the different subtypes of vessel-repairing cells.

Conditions

Diabetes Mellitus, Type 2

Keywords

Type 2 Diabetes; Vascular regeneration; Hematopoietic progenitor cells; Functionality; EndoPAT; Endothelial dysfunction; scRNA-seq; Colony formation assay; Secretome analyses

Outcome Measures

Primary Outcomes (1)

• Hematopoietic colony formation in ALDHhiSSClow regenerative cell subsets

  The capacity for total multipotent hematopoietic colony formation in ALDHhiSSClow regenerative cell subsets isolated from individuals living with T2D versus individuals not living with T2D.

  Baseline

Secondary Outcomes (2)

• Endothelial function

  Baseline

• Frequency and absolute number of circulating ALDHhiSSClowCD133+ progenitor cells

  Baseline

Study Arms (2)

Type 2 Diabetes

Participants living with type 2 diabetes for less than 10 years will be recruited.

No Diabetes

Participants not living with diabetes will be recruited.

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Individuals will be asked their self-representation of their gender identity.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants will be identified from primary care clinics in the Greater Toronto Area using paper-based and electronic medical records.

You may qualify if:

• Adults ≥18 years of age.
• Willing to provide written informed consent.
• Documented history of T2D
• No documented history of diabetes

You may not qualify if:

• Unable or unwilling to provide written informed consent or provide a peripheral blood sample.
• Any life-threatening disease expected to result in death within two years of consent.
• Any malignancy not considered cured (except basal cell carcinoma of the skin). An individual is considered cured if there has been no evidence of cancer recurrence for the five years prior to screening.
• Known severe liver disease.
• White blood cell count ≥15 x 10\^9/L.
• Active infectious disease requiring systemic antibiotic or anti-viral agents.
• Known acquired immunodeficiency syndrome such as HIV.
• Treated autoimmune disorders (e.g. T1D and LADA).
• On oral steroid therapy (e.g. prednisone or other corticosteroids) or other immunosuppressive agents (e.g. methotrexate).

Sponsors & Collaborators

• Canadian Medical and Surgical Knowledge Translation Research Group: lead
• Unity Health Toronto: collaborator
• University of Western Ontario, Canada: collaborator

Study Sites (1)

Diagnostic Assessment Centre

Scarborough Village, Ontario, M1S4N6, Canada

Location

Related Publications (25)

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• Hess DA, Verma S, Bhatt D, Bakbak E, Terenzi DC, Puar P, Cosentino F. Vascular repair and regeneration in cardiometabolic diseases. Eur Heart J. 2022 Feb 10;43(6):450-459. doi: 10.1093/eurheartj/ehab758.

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• Szmitko PE, Fedak PW, Weisel RD, Stewart DJ, Kutryk MJ, Verma S. Endothelial progenitor cells: new hope for a broken heart. Circulation. 2003 Jun 24;107(24):3093-100. doi: 10.1161/01.CIR.0000074242.66719.4A. No abstract available.

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• Dimmeler S. Regulation of bone marrow-derived vascular progenitor cell mobilization and maintenance. Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1088-93. doi: 10.1161/ATVBAHA.109.191668. Epub 2010 May 7.

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  PMID: 15862417 BACKGROUND

• Fadini GP, Boscaro E, de Kreutzenberg S, Agostini C, Seeger F, Dimmeler S, Zeiher A, Tiengo A, Avogaro A. Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes. Diabetes Care. 2010 May;33(5):1097-102. doi: 10.2337/dc09-1999. Epub 2010 Feb 11.

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• Mauch P, Hellman S. Loss of hematopoietic stem cell self-renewal after bone marrow transplantation. Blood. 1989 Aug 1;74(2):872-5.

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• Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development. 2014 Nov;141(22):4206-18. doi: 10.1242/dev.107086.

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• Moore MA. Does stem cell exhaustion result from combining hematopoietic growth factors with chemotherapy? If so, how do we prevent it? Blood. 1992 Jul 1;80(1):3-7. No abstract available.

  PMID: 1377052 BACKGROUND

• Mangialardi G, Spinetti G, Reni C, Madeddu P. Reactive oxygen species adversely impacts bone marrow microenvironment in diabetes. Antioxid Redox Signal. 2014 Oct 10;21(11):1620-33. doi: 10.1089/ars.2014.5944.

  PMID: 25089632 BACKGROUND

• Terenzi DC, Trac JZ, Teoh H, Gerstein HC, Bhatt DL, Al-Omran M, Verma S, Hess DA. Vascular Regenerative Cell Exhaustion in Diabetes: Translational Opportunities to Mitigate Cardiometabolic Risk. Trends Mol Med. 2019 Jul;25(7):640-655. doi: 10.1016/j.molmed.2019.03.006. Epub 2019 Apr 30.

  PMID: 31053416 BACKGROUND

• Hayden J, O'Donnell G, deLaunois I, O'Gorman C. Endothelial Peripheral Arterial Tonometry (Endo-PAT 2000) use in paediatric patients: a systematic review. BMJ Open. 2023 Jan 18;13(1):e062098. doi: 10.1136/bmjopen-2022-062098.

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• Li Q, Wang M, Zhang S, Jin M, Chen R, Luo Y, Sun X. Single-cell RNA sequencing in atherosclerosis: Mechanism and precision medicine. Front Pharmacol. 2022 Oct 4;13:977490. doi: 10.3389/fphar.2022.977490. eCollection 2022.

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• Kehl D, Generali M, Mallone A, Heller M, Uldry AC, Cheng P, Gantenbein B, Hoerstrup SP, Weber B. Proteomic analysis of human mesenchymal stromal cell secretomes: a systematic comparison of the angiogenic potential. NPJ Regen Med. 2019 Apr 16;4:8. doi: 10.1038/s41536-019-0070-y. eCollection 2019.

  PMID: 31016031 BACKGROUND

• GBD 2021 Diabetes Collaborators. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2023 Jul 15;402(10397):203-234. doi: 10.1016/S0140-6736(23)01301-6. Epub 2023 Jun 22.

  PMID: 37356446 RESULT

• Putman DM, Liu KY, Broughton HC, Bell GI, Hess DA. Umbilical cord blood-derived aldehyde dehydrogenase-expressing progenitor cells promote recovery from acute ischemic injury. Stem Cells. 2012 Oct;30(10):2248-60. doi: 10.1002/stem.1206.

  PMID: 22899443 RESULT

• Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, Nolta JA. Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood. 2004 Sep 15;104(6):1648-55. doi: 10.1182/blood-2004-02-0448. Epub 2004 Jun 3.

  PMID: 15178579 RESULT

• Fallon P, Gentry T, Balber AE, Boulware D, Janssen WE, Smilee R, Storms RW, Smith C. Mobilized peripheral blood SSCloALDHbr cells have the phenotypic and functional properties of primitive haematopoietic cells and their number correlates with engraftment following autologous transplantation. Br J Haematol. 2003 Jul;122(1):99-108. doi: 10.1046/j.1365-2141.2003.04357.x.

  PMID: 12823351 RESULT

• Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, Eades WC, Creer MH, Nolta JA. Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 2006 Mar 1;107(5):2162-9. doi: 10.1182/blood-2005-06-2284. Epub 2005 Nov 3.

  PMID: 16269619 RESULT

• Putman DM, Cooper TT, Sherman SE, Seneviratne AK, Hewitt M, Bell GI, Hess DA. Expansion of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells that Stimulate Limb Revascularization. Stem Cells Transl Med. 2017 Jul;6(7):1607-1619. doi: 10.1002/sctm.16-0472. Epub 2017 Jun 15.

  PMID: 28618138 RESULT

• Perin EC, Murphy MP, March KL, Bolli R, Loughran J, Yang PC, Leeper NJ, Dalman RL, Alexander J, Henry TD, Traverse JH, Pepine CJ, Anderson RD, Berceli S, Willerson JT, Muthupillai R, Gahremanpour A, Raveendran G, Velasquez O, Hare JM, Hernandez Schulman I, Kasi VS, Hiatt WR, Ambale-Venkatesh B, Lima JA, Taylor DA, Resende M, Gee AP, Durett AG, Bloom J, Richman S, G'Sell P, Williams S, Khan F, Gyang Ross E, Santoso MR, Goldman J, Leach D, Handberg E, Cheong B, Piece N, DiFede D, Bruhn-Ding B, Caldwell E, Bettencourt J, Lai D, Piller L, Simpson L, Cohen M, Sayre SL, Vojvodic RW, Moye L, Ebert RF, Simari RD, Hirsch AT; Cardiovascular Cell Therapy Research Network (CCTRN). Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells). Circulation. 2017 Apr 11;135(15):1417-1428. doi: 10.1161/CIRCULATIONAHA.116.025707. Epub 2017 Feb 16.

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• Terenzi DC, Al-Omran M, Quan A, Teoh H, Verma S, Hess DA. Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into the Prevention of Ischemic Complications in Diabetes. JACC Basic Transl Sci. 2018 Nov 5;4(1):98-112. doi: 10.1016/j.jacbts.2018.10.005. eCollection 2019 Feb.

  PMID: 30847424 RESULT

• Hess DA, Terenzi DC, Trac JZ, Quan A, Mason T, Al-Omran M, Bhatt DL, Dhingra N, Rotstein OD, Leiter LA, Zinman B, Sabongui S, Yan AT, Teoh H, Mazer CD, Connelly KA, Verma S. SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus. Cell Metab. 2019 Oct 1;30(4):609-613. doi: 10.1016/j.cmet.2019.08.015. Epub 2019 Aug 30.

  PMID: 31477497 RESULT

• Hess DA, Trac JZ, Glazer SA, Terenzi DC, Quan A, Teoh H, Al-Omran M, Bhatt DL, Mazer CD, Rotstein OD, Verma S. Vascular Risk Reduction in Obesity through Reduced Granulocyte Burden and Improved Angiogenic Monocyte Content following Bariatric Surgery. Cell Rep Med. 2020 May 19;1(2):100018. doi: 10.1016/j.xcrm.2020.100018. eCollection 2020 May 19.

  PMID: 33205058 RESULT

Related Links

• IDF Diabetes atlas, 10th ed.

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum samples will be retained for 5 years

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Subodh Verma, MD, PhD

  Unity Health Toronto

  PRINCIPAL INVESTIGATOR

• David A Hess, PhD

  Robarts Research Institute, London, Ontario

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fallon Dennis, BMSc

CONTACT

7057720021; fallon.dennis@mail.utoronto.ca

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 25, 2023
• First Posted: October 31, 2023
• Study Start: November 1, 2023
• Primary Completion: December 1, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: November 13, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)