ACE2 gene transfer ameliorates vasoreparative dysfunction in CD34+ cells derived from diabetic older adults
Shrinidh Joshi1, Ildamaris Montes de Oca2, Ahmad Maghrabi2
1Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, U.S.A.
Clinical Science (London, England : 1979)
|January 7, 2021
Summary
Diabetes impairs stem cell repair functions, worsening vascular disease. Increasing angiotensin-converting enzyme 2 (ACE2) in hematopoietic stem cells restores their revascularization potential, offering new therapeutic avenues for diabetic patients.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Metabolic Diseases
Background:
- Diabetes mellitus significantly elevates the risk of ischemic vascular diseases, particularly in older adults.
- Hematopoietic stem and progenitor cells (HSPCs), specifically CD34+ cells, possess regenerative capabilities crucial for revascularization.
- Diabetic conditions are known to impair the vasoreparative functions of these critical stem cells.
Purpose of the Study:
- To investigate the hypothesis that a diminished ACE2/ACE balance in hematopoietic stem/progenitor cells (HSPCs) contributes to diabetic dysfunction.
- To determine if enhancing ACE2 expression in HSPCs can restore their impaired reparative functions.
- To evaluate the therapeutic potential of ACE2-modified HSPCs in restoring blood flow in ischemic conditions.
Main Methods:
- Enumeration of CD34+ cells and determination of angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activities in blood samples from diabetic and nondiabetic individuals.
- Utilizing a lentiviral (LV) approach to increase soluble ACE2 protein expression in HSPCs.
- Assessing the revascularization potential of modified and unmodified HSPCs in mouse models of hindlimb ischemia (HLI), including in diabetic mice.
Main Results:
- Diabetic CD34+ cells exhibited attenuated revascularization capacity in nondiabetic mice compared to control cells.
- Lentiviral ACE2 modification of diabetic CD34+ cells completely restored blood flow recovery in nondiabetic mice.
- Hindlimb ischemia in diabetic mice showed poor recovery; however, LV-ACE2 modification of both control and diabetic CD34+ cells significantly improved blood flow recovery in these mice.
- In vitro treatment with Ang-(1-7) modulated the paracrine profile of diabetic CD34+ cells.
Conclusions:
- Vasoreparative dysfunction in CD34+ cells from older diabetic individuals is linked to an imbalance between ACE2 and ACE.
- Augmenting ACE2 expression in HSPCs is a promising strategy to enhance their revascularization potential.
- Targeting the ACE2 pathway in HSPCs may offer a novel therapeutic approach for treating ischemic vascular complications in diabetes.
