Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification

Carla Vicinanza, Iolanda Aquila, Mariangela Scalise, Francesca Cristiano, Fabiola Marino, Eleonora Cianflone, Teresa Mancuso, Pina Marotta, Walter Sacco, Fiona C. Lewis, Liam Couch, Victoria Shone, Giulia Gritti, Annalaura Torella, Andrew J. Smith, Cesare Mn Terracciano, Domenico Britti, Pierangelo Veltri, Ciro Indolfi, Bernardo Nadal-Ginard*Georgina Ellison-Hughes, Daniele Torella

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Citations (Scopus)
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Abstract

Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45pos c-kitpos cardiac cells were compared to CD45 neg (Lineage neg /Lin neg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (∼90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45pos CD31pos c-kitpos cells. In contrast, the Lin neg CD45 neg c-kitpos cardiac cell cohort, which represents >1/210% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kit neg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Lin neg c-kitpos cell-derived clones, which represent only 1-2% of total c-kitpos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Lin neg c-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC's myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs.

Original languageEnglish
Pages (from-to)2101-2116
Number of pages16
JournalCELL DEATH AND DIFFERENTIATION
Volume24
Issue number12
Early online date11 Aug 2017
DOIs
Publication statusPublished - Dec 2017

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