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Updated: May 22, 2026
Ultrasound-Guided Induced Pluripotent Stem Cell-Derived Cardiomyocyte Implantation in Myocardial Infarcted Mice
Published on: March 30, 2022
Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction
Alexander R Mackie1, Ekaterina Klyachko, Tina Thorne
1Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
Insights
Augmenting CD34+ stem cells with sonic hedgehog (Shh) improved cardiac function after myocardial infarction in mice. This enhancement was mediated by exosome-delivered Shh, offering a novel therapeutic strategy for ischemic cardiovascular disease.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Stem Cell Biology
Background:
- Ischemic cardiovascular disease is a major health issue in aging populations.
- Autologous stem cell therapy, particularly using CD34+ cells, shows promise for myocardial ischemia by promoting angiogenesis.
- The effectiveness of CD34+ cells diminishes with age and poor cardiovascular health due to reduced viability and angiogenic quality.
Purpose of the Study:
- To enhance the therapeutic potential of human CD34+ cells for ischemic cardiovascular disease.
- To investigate if augmenting CD34+ cell secretion of sonic hedgehog (Shh) can overcome age- and health-related declines.
- To explore Shh as a factor to improve the angiogenic capacity of CD34+ cells.
Main Methods:
- CD34+ cells were genetically modified to augment sonic hedgehog (Shh) secretion (CD34(Shh)).
- CD34(Shh) cells were injected into the border zone of mice following acute myocardial infarction.
- In vitro studies analyzed exosome-mediated Shh transfer and its effect on recipient cells' signaling pathways.
Main Results:
- Treatment with CD34(Shh) cells protected mice from cardiac functional decline and ventricular dilation post-myocardial infarction.
- CD34(Shh) treatment reduced infarct size and increased capillary density in the cardiac border zone.
- Exosomes derived from CD34(Shh) cells were found to transfer functional Shh protein, activating canonical Shh signaling in recipient cells.
Conclusions:
- Exosome-mediated delivery of Shh by modified CD34+ cells is a key mechanism for preserving cardiac function after myocardial infarction.
- This approach offers a potential strategy to improve stem cell therapy for ischemic heart disease.
- Shh augmentation enhances the angiogenic and protective effects of CD34+ cells through exosomal transfer.
Rationale:
Ischemic cardiovascular disease represents one of the largest epidemics currently facing the aging population. Current literature has illustrated the efficacy of autologous, stem cell therapies as novel strategies for treating these disorders. The CD34+ hematopoetic stem cell has shown significant promise in addressing myocardial ischemia by promoting angiogenesis that helps preserve the functionality of ischemic myocardium. Unfortunately, both viability and angiogenic quality of autologous CD34+ cells decline with advanced age and diminished cardiovascular health.
Objective:
To offset age- and health-related angiogenic declines in CD34+ cells, we explored whether the therapeutic efficacy of human CD34+ cells could be enhanced by augmenting their secretion of the known angiogenic factor, sonic hedgehog (Shh).
Methods And Results:
When injected into the border zone of mice after acute myocardial infarction, Shh-modified CD34+ cells (CD34(Shh)) protected against ventricular dilation and cardiac functional declines associated with acute myocardial infarction. Treatment with CD34(Shh) also reduced infarct size and increased border zone capillary density compared with unmodified CD34 cells or cells transfected with the empty vector. CD34(Shh) primarily store and secrete Shh protein in exosomes and this storage process appears to be cell-type specific. In vitro analysis of exosomes derived from CD34(Shh) revealed that (1) exosomes transfer Shh protein to other cell types, and (2) exosomal transfer of functional Shh elicits induction of the canonical Shh signaling pathway in recipient cells.
Conclusions:
Exosome-mediated delivery of Shh to ischemic myocardium represents a major mechanism explaining the observed preservation of cardiac function in mice treated with CD34(Shh) cells.
