c-Kit–Positive Cardiac Stem Cells Nested in Hypoxic Niches Are Activated by Stem Cell Factor Reversing the Aging Myopathy
Authors: Junghyun Kim
Noel Yan-Ki Chan
Emily Mangano
Maria Cimini
Donato Cappetta
Chiara Mangiaracina
Annarosa Leri
Barbara Ogórek
Mario Ricciardi
Mark A Perrella
Fumihiro Sanada
Toru Hosoda
Emeka Ifedigbo
Ewa Wybieralska
Anna Czarna
Jan Kajstura
Polina Goichberg
Ada Pesapane
Sergio Signore
Augustine M Choi
Giulia Borghetti
Andrea Sorrentino
Marcello Rota
Kazuya Isobe
Piero Anversa
Journal: Circulation Research (2014)
Discipline: CLINICAL MEDICINE
Keywords: stem cell factor.
Affiliations: From the Departments of Anesthesia (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.) and Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., E.I., M.A.P., P.G., J.K., T.H., M. Rota, P.A., A.L.), and Divisions of Cardiovascular Medicine (F.S., J.K., A.M.C., N.Y.-.K.C., S.S., B.O., K.I., E.W., G.B., A.P., A.S., E.M., D.C., C.M., M. Ricciardi, M.C., P.G., J.K., T.H., M. Rota, P.A., A.L.), Pulmonary and Critical Care Medicine (E.I., M.A.P., A.M.C.), and Newborn Medicine (M.A.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Abstract:  Rationale: Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell 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 re-enter 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 suggest that a pool of functionally competent CSCs persists in the senescent heart and that this stem cell compartment can promote myocyte regeneration effectively, partly correcting the aging myopathy. 

Retracted: No

PubPeer comments:
 it is unlikely that cardiac stem cells exist. https: www.statnews.com 2018 10 14 harvard-brigham-retractions-stem-cell , 
 https: www.nytimes.com 2018 10 29 health dr-piero-anversa-harvard-retraction.html , 
 https: retractionwatch.com 2018 12 13 anversa-cardiac-stem-cell-lab-earns-13-retractions , 
 2015 correction. https: www.ahajournals.org doi 10.1161 RES.0000000000000064 Questions were raised about Figures 3A, 3C, and 4B in the article. The antibody employed for the detection of Ki67 was a rat monoclonal while the antibodies utilized to identify Nkx2.5 and GATA4 were goat polyclonal. It was appropriate to use the same isotype control for Nkx2.5 and GATA4, but a different isotype control was introduced for the analysis of Ki67. A mistake was made in the assembly of Figures 3A, 3C, and 4B. The similarity in the FACS plots resulted in an error, which has been corrected in the revised figures. For clarity, plots collected at the same time have been selected. The legends to Figures 3A, 3C, and 4B remain unchanged. The authors regret this circumstance.  The similarity in the FACS plots resulted in an error sounds like image duplication. , 
 Comparing the flow cytometry panels in the original, uncorrected paper shows some unexpected similarities between panels in Figures 3A, 3C, and 4C. These panels appear to be labeled differently. Similar looking quadrants are highlighted below with boxes of the same color. These similarities are not identities. Instead, some of the constellations of the dots appear similar while other dots are missing. Because only some, but not all dots are identical across panels, it seems very unlikely that this could have happened by an honest error, such as the inadvertent inclusion of the same panel twice. Could the authors please provide a thorough explanation of what error exactly caused these panels to look so similar? ![file] ,