c-Kit–Positive Cardiac Stem Cells Nested in Hypoxic Niches Are Activated by Stem Cell Factor Reversing the Aging Myopathy

Abstract

Rationale Hypoxia favors stem cell quiescence, while normoxia is required for their activation; but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown. Objective A balance between hypoxic and normoxic CSCs may be present in the young heart, although this homeostatic control may be disrupted with aging. Defects in tissue oxygenation occur in the old myocardium, and this phenomenon may expand the pool of hypoxic CSCs, which are no longer involved in myocyte renewal. Methods and Results Here we show that the senescent heart is characterized by an increased number of quiescent CSCs with intact telomeres that cannot reenter the cell cycle and form a differentiated progeny. Conversely, myocyte replacement is controlled only by frequently dividing CSCs with shortened telomeres; these CSCs generate a myocyte population that is chronologically young but phenotypically old. Telomere dysfunction dictates their actual age and mechanical behavior. However, the residual subset of quiescent young CSCs can be stimulated in situ by stem cell factor reversing the aging myopathy. Conclusions Our findings support the notion that strategies targeting CSC activation and growth interfere with the manifestations of myocardial aging in an animal model. Although caution has to be exercised in the translation of animal studies to human beings, our data strongly suggests that a pool of functionally-competent CSCs persists in the senescent heart and this stem cell compartment can promote myocyte regeneration effectively, correcting partly the aging myopathy.

Myocardial Telocyte-Like Cells: A Review Including New Evidence

“…In mouse hearts, the myocardium was found to harbor c-kit+ cardiac stem cells that were clustered in heterogeneous niches, and, with aging, the fraction of these senescent cardiac stem cells was found to increase [Sanada et al, 2014]. The hypoxic cardiac stem cell niches can be activated by the stem cell factor [Sanada et al, 2014], namely the c-kit ligand.…”

Factors for C-Kit Expression in Cardiac Outgrowth Cells and Human Heart Tissue

“…A potential reason may be differences in the oxygen concentration in the blood that passed through the tissues; the blood that passed through the RA had a much lower concentration of oxygen than the blood that passed through the LA. CSCs exist in a niche in which oxygen is low, 26) implying better circumstances in RA tissue, especially on the endocardium side. Furthermore, the dominant transcription factors during embryonic stages are different between the atrium and ventricle, as well as between the right and left atrium.…”

Where are Cell-Based Therapies Heading? Current Limitations and Future Directions

“…27 Hypoxia stimulation activates pro-survival pathways via phosphorylation of Akt and p38 resulting in HIF1alpha activation. 23,28 Hypoxic preconditioning of MSCs 20 or cardiac stem cells (CSCs) 29 enhanced therapeutic effects in an ischemia model.…”