Allan Pulliam

Introduction. Hypoplastic left heart syndrome (HLHS) is the most common and one of the most severe/difficult to treat forms of congenital heart disease (CHD).¹ Success of a series of three complex surgeries and therefore patient life expectancy are dependent upon the right ventricle’s ability to function as the sole systemic pump, which has a limited durability.² Stem cell therapy is being researched as a hopeful approach to the management of right ventricular dysfunction associated with HLHS patients.¹ We review one promising study that hypothesizes follicular estradiol (E2) could promote/improve the homing and retention of mesenchymal stem cells (MSCs) in injured heart tissue, due to E2’s known beneficial proangiogenic effects on the cardiovascular system.³ The goal of that investigation was to identify whether hormone supplementation could improve stem cell integration and angiogenesis in post-surgery HLHS patients’ cardiac tissue. Methods. The beneficial effects of E2 on MSC proliferation in murine heart slices was studied using xCELLigence real-time cell-impedance system, and Trypan blue exclusion and CMFDA staining were used to confirm increased stem cell proliferation.³ MSC-induced angiogenesis in vivo was observed with a matrigel plug assay, where plugs containing MSCs or MSCs + E2 were implanted in C57B1/6 mice, and capillary formation was examined after 7 days. Changes in protein expression were measured via Western blotting, ELISA/Luminex, and proteomic analysis.³ Results. E2 treatment induced expression of VEGF-A genes (known to promote angiogenesis), and increased expression of VEGF protein.³ Matrigel plugs containing MSCs alone or MSCs with E2 both yielded capillary formation, but no neovascularization in gels lacking MSCs. A significantly higher number of capillaries developed in the MSC + E2 matrigel plugs, compared to the MSC alone plugs, providing evidence for increased angiogenesis by MSCs treated with E2.³ Another study examined estrogen combination therapy (transdermal estrogen gel and oral aspirin) used in patients with intrauterine adhesion disease following transcervical resection of adhesion and compared to a control group (estrogen-only therapy). Compared to the control, those taking oral aspirin along with estrogen demonstrated increased angiogenesis, which improved rehabilitation via upregulation of VEGF.⁴ Conclusions. Studies support hormone supplementation (such as follicular estradiol) for enhancement of MSC-induced angiogenesis, because of increased VEGF expression.^3,4 MSC therapy (delivered via direct intramyocardial injection) along with estrogen combination treatment could serve to promote angiogenesis and stem cell integration by upregulating VEGF pathways, serving as an innovative intervention for congenital heart diseases such as HLHS.

1. Ambastha C, Bittle GJ, Morales D, et al. Regenerative medicine therapy for single ventricle congenital heart disease. Transl Pediatr. 2018;7(2):176-187. doi:10.21037/tp.2018.04.01
2. Metcalf MK, Rychik J. Outcomes in Hypoplastic Left Heart Syndrome. Pediatr Clin North Am. 2020;67(5):945-962. doi:10.1016/j.pcl.2020.06.008
3. Mihai MC, Popa MA, Suica VI, et al. Mechanism of 17β-estradiol stimulated integration of human mesenchymal stem cells in heart tissue. J Mol Cell Cardiol. 2019;133:115-124. doi:10.1016/j.yjmcc.2019.06.007
4. Chi Y, He P, Lei L, et al. Transdermal estrogen gel and oral aspirin combination therapy improves fertility prognosis via the promotion of endometrial receptivity in moderate to severe intrauterine adhesion. Mol Med Rep. 2018;17(5):6337-6344. doi:10.3892/mmr.2018.8685