GPC3-mediated metabolic rewiring of diabetic mesenchymal stromal cells enhances their cardioprotective functions via PKM2 activation
Darukeshwara Joladarashi,
Charan Thej,
Vandana Mallaredy,
Ajit Magadum,
Maria Cimini,
Carolina Gonzalez,
May Truongcao,
Joseph T. Nigro,
Manveen K. Sethi,
Andrew A. Gibb,
Cindy Benedict,
Walter J. Koch,
Raj Kishore
Affiliations
Darukeshwara Joladarashi
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Charan Thej
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Vandana Mallaredy
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Ajit Magadum
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Maria Cimini
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Carolina Gonzalez
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
May Truongcao
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Joseph T. Nigro
Center for Biomedical Mass Spectrometry, Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
Manveen K. Sethi
Center for Biomedical Mass Spectrometry, Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
Andrew A. Gibb
Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville, 580 South Preston Street, Louisville, KY, USA
Cindy Benedict
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Walter J. Koch
Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
Raj Kishore
Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Corresponding author
Summary: Mesenchymal stromal cells (MSC) are promising stem cell therapy for treating cardiovascular and other degenerative diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. Despite numerous studies, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction remains inadequately perceived. We demonstrated that the transplantation of diabetic-MSC (db/db-MSC) into the ischemic myocardium of mice does not confer cardiac benefit post-MI. Metabolomic studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that glypican-3 (GPC3), a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC and is involved in metabolic alterations in db/db-MSC via pyruvate kinase M2 (PKM2) activation. GPC3-knockdown reprogrammed-db/db-MSC restored their energy metabolic rates, immunomodulation, angiogenesis, and cardiac reparative activities. Together, these data indicate that GPC3-metabolic reprogramming in diabetic MSC may represent a strategy to enhance MSC-based therapeutics for myocardial repair in diabetic patients.
