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J Thorac Cardiovasc Surg 2006;132:1272-1279
© 2006 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Overexpression of integrin-linked kinase induces cardiac stem cell expansion

^a Cardiovascular Research, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
^b Cancer Research Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication April 28, 2006; revisions received June 29, 2006; accepted for publication August 3, 2006.

^_* Address for reprints: J. G. Coles, MD, Division of Cardiovascular Surgery, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada. (Email: john.coles{at}sickkids.ca).

OBJECTIVE: Recent evidence suggests that the adult heart contains stem cells that are capable of self-renewal as well as multilineage differentiation. However, their inherent capacity for self-renewal is limiting to cell replacement applications. Integrin-linked kinase is a multifunctional protein kinase that activates Wnt target genes implicated in the symmetric replication of embryonic stem cells.

METHODS: Primary cultures derived from human fetal cardiac tissue (19-22 weeks’ gestation) were grown in serum-free media and evaluated for the presence of cardiac progenitor cells. The effect of integrin-linked kinase was ascertained by adenoviral overexpression.

RESULTS: Cultures infected with wild-type integrin-linked kinase yielded a significant (P = .001), approximately 5-fold increase in both the absolute number and the frequency of c-Kit-positive, myosin-negative cells. Cardiospheres, comprised on morphologically homogeneous, anchorage-independent cells, were reproducibly present at days 7 to 10 and formed derivative cardiospheres in multiple passages. Integrin-linked kinase infection of primary cardiac cell cultures resulted in a greater number of primary spheres at each cell density tested, compared with untreated and virus controls (P = .001). Secondary spheres transferred to differentiation medium and 5-aza-deoxycytodine (10 µmol/L) generated cells exhibiting biochemical evidence of differentiation into cardiomyocytes, smooth muscle cells, and endothelial cells.

CONCLUSIONS: This study demonstrates that self-renewing cardiospheres generated from human fetal cardiac cells are composed of cells exhibiting the properties of stem cells, including the capacity for self-renewal and multilineage differentiation. Our results suggest that integrin-linked kinase promotes stem cell amplification and can be applied therapeutically to overcome a major limitation in the field of cardiac regenerative medicine.

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Discussion
J. Thorac. Cardiovasc. Surg. 2006 132: 1279. [Extract] [Full Text] [PDF]