Bone Marrow and Wharton's Jelly Mesenchymal Stromal Cells Are Ineffective for Myocardial Repair in an Immunodeficient Rat Model of Chronic Ischemic Cardiomyopathy

Overview

Journal Stem Cell Rev Rep

Publisher Springer

Specialty Cell Biology

Date 2023 Jul 27

PMID 37500831

Authors

Xian-Liang Tang

Marjan Nasr

Shirong Zheng

Taylor Zoubul

Jonah K Stephan

Shizuka Uchida

Richa Singhal

Aisha Khan

Anna Gumpert

Roberto Bolli

Marcin Wysoczynski

Affiliations

Soon will be listed here.

Abstract

Background: Although cell therapy provides benefits for outcomes of heart failure, the most optimal cell type to be used clinically remains unknown. Most of the cell products used for therapy in humans require in vitro expansion to obtain a suitable number of cells for treatment; however, the clinical background of the donor and limited starting material may result in the impaired proliferative and reparative capacity of the cells expanded in vitro. Wharton's jelly mesenchymal cells (WJ MSCs) provide a multitude of advantages over adult tissue-derived cell products for therapy. These include large starting tissue material, superior proliferative capacity, and disease-free donors. Thus, WJ MSC if effective would be the most optimal cell source for clinical use.

Objectives: This study evaluated the therapeutic efficacy of Wharton's jelly (WJ) and bone marrow (BM) mesenchymal stromal cells (MSCs) in chronic ischemic cardiomyopathy in rats.

Methods: Human WJ MSCs and BM MSCs were expanded in vitro, characterized, and evaluated for therapeutic efficacy in a immunodeficient rat model of ischemic cardiomyopathy. Cardiac function was evaluated with hemodynamics and echocardiography. The extent of cardiac fibrosis, hypertrophy, and inflammation was assessed with histological analysis.

Results: In vitro analysis revealed that WJ MSCs and BM MSCs are morphologically and immunophenotypically indistinguishable. Nevertheless, the functional analysis showed that WJ MSCs have a superior proliferative capacity, less senescent phenotype, and distinct transcriptomic profile compared to BM MSC. WJ MSCs and BM MSC injected in rat hearts chronically after MI produced a small, but not significant improvement in heart structure and function. Histological analysis showed no difference in the scar size, collagen content, cardiomyocyte cross-sectional area, and immune cell count.

Conclusions: Human WJ and BM MSC have a small but not significant effect on cardiac structure and function when injected intramyocardially in immunodeficient rats chronically after MI.

Citing Articles

Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischaemic cardiomyopathy.

Tang X, Wysoczynski M, Gumpert A, Solanki M, Li Y, Wu W Cardiovasc Res. 2024; 120(15):1939-1952.

PMID: 39163570 PMC: 11630033. DOI: 10.1093/cvr/cvae173.

References

Hou T, Xu J, Wu X, Xie Z, Luo F, Zhang Z . Umbilical cord Wharton's Jelly: a new potential cell source of mesenchymal stromal cells for bone tissue engineering. Tissue Eng Part A. 2009; 15(9):2325-34. DOI: 10.1089/ten.tea.2008.0402. View

Banerjee M, Bolli R, Hare J . Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions. Circ Res. 2018; 123(2):266-287. PMC: 8742222. DOI: 10.1161/CIRCRESAHA.118.311217. View

Moore 4th J, Tang X, Zhao J, Fischer A, Wu W, Uchida S . Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy. Basic Res Cardiol. 2018; 114(1):3. PMC: 6335654. DOI: 10.1007/s00395-018-0710-1. View

Hong K, Guo Y, Li Q, Cao P, Al-Maqtari T, Vajravelu B . c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One. 2014; 9(5):e96725. PMC: 4013035. DOI: 10.1371/journal.pone.0096725. View

Heidel J, Fischer A, Tang X, Sadri G, Wu W, Moisa C . The Effect of Cardiogenic Factors on Cardiac Mesenchymal Cell Anti-Fibrogenic Paracrine Signaling and Therapeutic Performance. Theranostics. 2020; 10(4):1514-1530. PMC: 6993223. DOI: 10.7150/thno.41000. View

Bartolucci J, Verdugo F, Gonzalez P, Larrea R, Abarzua E, Goset C . Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord.... Circ Res. 2017; 121(10):1192-1204. PMC: 6372053. DOI: 10.1161/CIRCRESAHA.117.310712. View

Nekanti U, Dastidar S, Venugopal P, Totey S, Ta M . Increased proliferation and analysis of differential gene expression in human Wharton's jelly-derived mesenchymal stromal cells under hypoxia. Int J Biol Sci. 2010; 6(5):499-512. PMC: 2945278. DOI: 10.7150/ijbs.6.499. View

Uthamalingam S, Patvardhan E, Subramanian S, Ahmed W, Martin W, Daley M . Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. Am J Cardiol. 2011; 107(3):433-8. DOI: 10.1016/j.amjcard.2010.09.039. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

10.

Fong C, Chak L, Biswas A, Tan J, Gauthaman K, Chan W . Human Wharton's jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev Rep. 2010; 7(1):1-16. DOI: 10.1007/s12015-010-9166-x. View

11.

Behfar A, Yamada S, Crespo-Diaz R, Nesbitt J, Rowe L, Perez-Terzic C . Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol. 2010; 56(9):721-34. PMC: 2932958. DOI: 10.1016/j.jacc.2010.03.066. View

12.

Gao L, Chen Y, Zhang N, Yang X, Liu H, Wang Z . Intracoronary infusion of Wharton's jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med. 2015; 13:162. PMC: 4499169. DOI: 10.1186/s12916-015-0399-z. View

13.

Batsali A, Kastrinaki M, Papadaki H, Pontikoglou C . Mesenchymal stem cells derived from Wharton's Jelly of the umbilical cord: biological properties and emerging clinical applications. Curr Stem Cell Res Ther. 2013; 8(2):144-55. DOI: 10.2174/1574888x11308020005. View

14.

Zhou C, Yang B, Tian Y, Jiao H, Zheng W, Wang J . Immunomodulatory effect of human umbilical cord Wharton's jelly-derived mesenchymal stem cells on lymphocytes. Cell Immunol. 2011; 272(1):33-8. PMC: 3235326. DOI: 10.1016/j.cellimm.2011.09.010. View

15.

Seshareddy K, Troyer D, Weiss M . Method to isolate mesenchymal-like cells from Wharton's Jelly of umbilical cord. Methods Cell Biol. 2008; 86:101-19. DOI: 10.1016/S0091-679X(08)00006-X. View

16.

Liu C, Huang H, Sun P, Ma S, Liu A, Xue J . Human Umbilical Cord-Derived Mesenchymal Stromal Cells Improve Left Ventricular Function, Perfusion, and Remodeling in a Porcine Model of Chronic Myocardial Ischemia. Stem Cells Transl Med. 2016; 5(8):1004-13. PMC: 4954453. DOI: 10.5966/sctm.2015-0298. View

17.

Tang X, Nakamura S, Li Q, Wysoczynski M, Gumpert A, Wu W . Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose. J Am Heart Assoc. 2018; 7(4). PMC: 5850187. DOI: 10.1161/JAHA.117.007400. View

18.

Tang X, Li Q, Rokosh G, Sanganalmath S, Chen N, Ou Q . Long-Term Outcome of Administration of c-kit(POS) Cardiac Progenitor Cells After Acute Myocardial Infarction: Transplanted Cells Do not Become Cardiomyocytes, but Structural and Functional Improvement and Proliferation of Endogenous Cells Persist.... Circ Res. 2016; 118(7):1091-105. PMC: 4818175. DOI: 10.1161/CIRCRESAHA.115.307647. View

19.

Bansal S, Ismahil M, Goel M, Patel B, Hamid T, Rokosh G . Activated T Lymphocytes are Essential Drivers of Pathological Remodeling in Ischemic Heart Failure. Circ Heart Fail. 2017; 10(3):e003688. PMC: 5331621. DOI: 10.1161/CIRCHEARTFAILURE.116.003688. View

20.

Bolli R, Mitrani R, Hare J, Pepine C, Perin E, Willerson J . A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021; 23(4):661-674. PMC: 8357352. DOI: 10.1002/ejhf.2178. View