Evidence for Minimal Cardiogenic Potential of Stem Cell Antigen 1–Positive Cells in the Adult Mouse Heart

Neidig, Lauren E.; Weinberger, Florian; Palpant, Nathan J.; Mignone, John L.; Martinson, Amy; Sorensen, Daniel W.; Bender, Ingrid; Nemoto, Natsumi; Reinecke, Hans; Pabon, Lil; Molkentin, Jeffery D.; Murry, Charles E.; Berlo, Jop H. van

doi:10.1161/circulationaha.118.035273

Cited by 35 publications

(18 citation statements)

References 6 publications

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“…Lineage tracing of Sca-1 expressing cells in the mouse heart revealed only a very limited ability to significantly contribute new cardiomyocytes to the heart after MI in the mouse. In fact, they demonstrated a mostly endothelial expression pattern in Sca-1 mCm R26 dTomato hearts that colocalized with CD31 expression [31]. Tang et al [32] by targeting endogenous Sca1 + cells in Sca1-2A-CreER; R26-tdTomato mice through pulse labeling experiments showed that 94.25 ± 0.54% tdTomato + cells were CD31 + endothelial cells, indicating that most Sca1 + cells adopt an endothelial cell fate during cardiac homeostasis.…”

Section: Discussionmentioning

confidence: 97%

Cardioprotective Potential of Human Endothelial-Colony Forming Cells from Diabetic and Nondiabetic Donors

Deutsch

Brunner

Grabmaier

et al. 2020

Cells

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Objective: The potential therapeutic role of endothelial progenitor cells (EPCs) in ischemic heart disease for myocardial repair and regeneration is subject to intense investigation. The aim of the study was to investigate the proregenerative potential of human endothelial colony-forming cells (huECFCs), a very homogenous and highly proliferative endothelial progenitor cell subpopulation, in a myocardial infarction (MI) model of severe combined immunodeficiency (SCID) mice. Methods: CD34+ peripheral blood mononuclear cells were isolated from patient blood samples using immunomagnetic beads. For generating ECFCs, CD34+ cells were plated on fibronectin-coated dishes and were expanded by culture in endothelial-specific cell medium. Either huECFCs (5 × 105) or control medium were injected into the peri-infarct region after surgical MI induction in SCID/beige mice. Hemodynamic function was assessed invasively by conductance micromanometry 30 days post-MI. Hearts of sacrificed animals were analyzed by immunohistochemistry to assess cell fate, infarct size, and neovascularization (huECFCs n = 15 vs. control n = 10). Flow-cytometric analysis of enzymatically digested whole heart tissue was used to analyze different subsets of migrated CD34+/CD45+ peripheral mononuclear cells as well as CD34−/CD45− cardiac-resident stem cells two days post-MI (huECFCs n = 10 vs. control n = 6). Results: Transplantation of human ECFCs after MI improved left ventricular (LV) function at day 30 post-MI (LVEF: 30.43 ± 1.20% vs. 22.61 ± 1.73%, p < 0.001; ΔP/ΔTmax 5202.28 ± 316.68 mmHg/s vs. 3896.24 ± 534.95 mmHg/s, p < 0.05) when compared to controls. In addition, a significantly reduced infarct size (50.3 ± 4.5% vs. 66.1 ± 4.3%, p < 0.05) was seen in huECFC treated animals compared to controls. Immunohistochemistry failed to show integration and survival of transplanted cells. However, anti-CD31 immunohistochemistry demonstrated an increased vascular density within the infarct border zone (8.6 ± 0.4 CD31+ capillaries per HPF vs. 6.2 ± 0.5 CD31+ capillaries per HPF, p < 0.001). Flow cytometry at day two post-MI showed a trend towards increased myocardial homing of CD45+/CD34+ mononuclear cells (1.1 ± 0.3% vs. 0.7 ± 0.1%, p = 0.2). Interestingly, we detected a significant increase in the population of CD34−/CD45−/Sca1+ cardiac resident stem cells (11.7 ± 1.7% vs. 4.7 ± 1.7%, p < 0.01). In a subgroup analysis no significant differences were seen in the cardioprotective effects of huECFCs derived from diabetic or nondiabetic patients. Conclusions: In a murine model of myocardial infarction in SCID mice, transplantation of huECFCs ameliorated myocardial function by attenuation of adverse post-MI remodeling, presumably through paracrine effects. Cardiac repair is enhanced by increasing myocardial neovascularization and the pool of Sca1+ cardiac resident stem cells. The use of huECFCs for treating ischemic heart disease warrants further investigation.

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Section: Discussionmentioning

confidence: 97%

Cardioprotective Potential of Human Endothelial-Colony Forming Cells from Diabetic and Nondiabetic Donors

Deutsch

Brunner

Grabmaier

et al. 2020

Cells

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“…However, several studies demonstrated that c‐kit + cells in the heart are unable to contribute to new cardiomyocytes (Molkentin, 2014; van Berlo & Molkentin, 2016; van Berlo et al, 2014). Recently, two groups of research reported that sca‐1 + cells rarely became cardiomyocytes and instead become endothelial cells in the heart (Neidig et al, 2018; Zhang et al, 2018). It is possible that these c‐kit + cells or sca‐1 + cells secrete paracrine factors that help repair injured heart cells, a similar mechanism underlying MSC effect on the improvement of cardiac function.…”

Section: Cell Types Used For Cell Therapy Of Cardiac Regenerationmentioning

confidence: 99%

Arrhythmogenic risks of stem cell replacement therapy for cardiovascular diseases

Chen

Huang

Singh

et al. 2020

Journal Cellular Physiology

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Ischemic heart disease and congestive heart failure are major contributors to high morbidity and mortality. Approximately 1.5 million cases of myocardial infarction occur annually in the United States; the yearly incidence rate is approximately 600 cases per 100,000 people. Although significant progress to improve the survival rate has been made by medications and implantable medical devices, damaged cardiomyocytes are unable to be recovered by current treatment strategies. After almost two decades of research, stem cell therapy has become a very promising approach to generate new cardiomyocytes and enhance the function of the heart.Along with clinical trials with stem cells conducted in cardiac regeneration, concerns regarding safety and potential risks have emerged. One of the contentious issues is the electrical dysfunctions of cardiomyocytes and cardiac arrhythmia after stem cell therapy. In this review, we focus on the cell sources currently used for stem cell therapy and discuss related arrhythmogenic risk.

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“…Some reports, on the other hand, have altogether refuted their contribution. However, it is beyond the scope of this review (Beltrami et al, 2003;Garry and Olson, 2006;Lyngbaek et al, 2007;Kehat and Molkentin, 2010;Ellison et al, 2013;Molkentin and Houser, 2013;Xin et al, 2013;Molkentin, 2014;Nadal-Ginard et al, 2014;Molkentin, 2014, 2016;Kanisicak et al, 2017;Maliken et al, 2018;Neidig et al, 2018;Tang et al, 2018a;Vagnozzi et al, 2018;Ni et al, 2019). It is a well-established fact that most of the progenitor cells require transcription factors for differentiation and proliferation.…”

Section: Hsc Derived Cardiomyocytesmentioning

confidence: 99%

Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology

et al. 2020

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Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.

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Evidence for Minimal Cardiogenic Potential of Stem Cell Antigen 1–Positive Cells in the Adult Mouse Heart

Cited by 35 publications

References 6 publications

Cardioprotective Potential of Human Endothelial-Colony Forming Cells from Diabetic and Nondiabetic Donors

Cardioprotective Potential of Human Endothelial-Colony Forming Cells from Diabetic and Nondiabetic Donors

Arrhythmogenic risks of stem cell replacement therapy for cardiovascular diseases

Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology

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