Machine Learning Identifies Distinct Treg-Mediated Remodeling in HFpEF Hearts Treated with Neonatal Mesenchymal Stem Cells and Their Secretome
Year: 2026
Type: preprint
Abstract: Background Heart failure with preserved ejection fraction (HFpEF) remains a major therapeutic challenge due to its complex pathophysiology and pronounced heterogeneity. Regenerative approaches using neonatal mesenchymal stromal cells (nMSCs) and their secretome (SEC) have shown promise in other heart failure contexts. Objectives However, the effect of these therapies in HFpEF, and the underlying molecular mechanisms and causal pathways remain poorly understood. Methods HFpEF was established in two distinct murine models, followed by treatment with either nMSCs or SEC. Functional and histological endpoints were assessed. We developed a novel machine learning framework, VIPcell, which integrates data augmentation, Partial Least Squares (PLS) regression, and causal structure inference to identify genes causally linked to cardiac function using single-nucleus RNA sequencing (snRNA-seq) data. VIPcell was applied to heart tissues from treated HFpEF animals to uncover key regulators of cardiac remodeling. Results Both nMSC and SEC therapies significantly improved diastolic function in two independent rodent HFpEF models. These improvements were associated with reduced inflammation, attenuated myocardial fibrosis, and improved exercise capacity. Intercellular communication analysis revealed widespread, system-level signaling in nMSC-treated hearts, compared to more localized endothelial–cardiomyocyte crosstalk in SEC-treated hearts. Causal inference via VIPcell suggested overlapping upstream regulators in both treatment groups, particularly genes involved in regulatory T cell (T reg ) biology and immunomodulatory signaling pathways, including FOXO signaling, NLRP3 inflammasome inhibition, and Tie2 activation. In vivo validation confirmed selective expansion of T regs following nMSC and SEC therapy. In vitro, nMSCs induced significantly greater T reg expansion compared to multiple adult stem cell types. Critically, chemical depletion of T regs abrogated the therapeutic effects of both treatments, establishing T regs as central mediators of diastolic function recovery in the HFpEF preclinical model. Conclusions nMSC and SEC therapies improve diastolic function in HFpEF through distinct remodeling mechanisms converging on T reg -mediated immune modulation. VIPcell supported identification of causal regulators, highlighting T reg -related signaling as a key driver of myocardial recovery in HFpEF. These findings offer mechanistic insight into cellular therapies for HFpEF and support the development of targeted, T reg -focused interventions.
Authors: Zhi-Dong Ge, Jonghyeuk Han, Felipe Takaesu, Rachana Mishra, Sudhish Sharma, Ling Chen, Xuebin Fu, Mallory Filipp, Ching Man Wai, Ning-Yi Shao, Anshuman Sinha, Progyaparamita Saha, Akash Puvvala, Luna Ventura, Sonia Thakkar, Agata Bileweska, Artur Stefenwicz, Sameer Ahmad Guru, Muthukumar Gunasekaran, Evan Yang, Buddhadeb Dawn, Peixin Yang, Sanjiv J. Shah, Edward Thorp, Michael E. Davis, Sunjay Kaushal
Institutions: Northwestern University, Lurie Children's Hospital, Georgia Institute of Technology, Emory University, The Wallace H. Coulter Department of Biomedical Engineering, University of Macau, Stony Brook University, University of Nevada, Las Vegas, University of Maryland, Baltimore, Northwestern Memorial Hospital, Children's Healthcare of Atlanta
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G8754514528
OpenAlex ID: W7126247652