Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mohsin, Sadia; Troupes, Constantine D; Starosta, Timothy; Sharp, Thomas E; Agra, Elorm J.; Smith, Shavonn; Duran, Jason; Zalavadia, Neil; Zhou, Yan; Kubo, Hajime; Berretta, Remus; Houser, Steven R.

doi:10.1161/circresaha.115.307362

Cited by 30 publications

(39 citation statements)

References 41 publications

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“…These early clinical trial results cast doubts as to whether there were any beneficial effects of bone marrow therapy for MI due to fleeting positive impact upon heart function long-term and wide-ranging efficacy [58], prompting a need for additional preclinical studies focused upon these and other stem cell treatment options [59]. One of the recent studies involves swine cortical bone stem cells (CBSCs), demonstrating increased proliferation, migration, cardiac lineage commitment, functional gap junctions and differential response to ATP and histamine stimuli as compared to MSCs or cardiac-derived stem cells [60]. …”

Section: Current Status Of Adult Stem Cell Therapiesmentioning

confidence: 99%

Empowering Adult Stem Cells for Myocardial Regeneration V2.0

Broughton

Sussman

2016

Circulation Research

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Much has changed since our survey of the landscape for myocardial regeneration powered by adult stem cells four years ago (Mohsin et al., Empowering adult stem cells for myocardial regeneration. Circ Res. 2011; 109(12):1415–1428) [1]. The intervening years since that first review has witnessed an explosive expansion of studies that advance both understanding and implementation of adult stem cells in promoting myocardial repair. Painstaking research from innumerable laboratories throughout the world is prying open doors that may lead to restoration of myocardial structure and function in the wake of pathologic injury. This global effort has produced deeper mechanistic comprehension coupled with an evolving appreciation for the complexity of myocardial regeneration in the adult context. Undaunted by both known and (as yet) unknown challenges, pursuit of myocardial regenerative medicine mediated by adult stem cell therapy has gathered momentum fueled by tantalizing clues and visionary goals. This concise review takes a somewhat different perspective than our initial treatise, taking stock of the business sector that has become an integral part of the field while concurrently updating “state of affairs” in cutting edge research. Looking retrospectively at advancement over the years as all reviews eventually must, the fundamental lesson to be learned is best explained by Jonatan Mårtensson: “Success will never be a big step in the future. Success is a small step taken just now.”

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Section: Current Status Of Adult Stem Cell Therapiesmentioning

confidence: 99%

Empowering Adult Stem Cells for Myocardial Regeneration V2.0

Broughton

Sussman

2016

Circulation Research

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“…MSC-based therapy, originating from BM-, adipose tissue-, or umbilical cord-cells, continues to gain consent and appeal, because of the large body of preclinical evidence supporting higher paracrine cardioreparative potential 4 . However, poor survival of donated stem cells and failure of stem cell engraftment in the damaged organ occurs within the first days after delivery, posing a significant challenge in the field 1 . A complete understanding of the mechanisms enhancing MSC migration and survival in the microenvironment of the injured myocardium is imperative, to improve both MSC repair capacity and therapeutic application.…”

Section: Discussionmentioning

confidence: 99%

“…Myocardial infarction results in compromised myocardial function and heart failure (HF), due to acute and chronic loss of cardiomyocytes 1 . Because adult mammalian hearts have very limited regenerative capacity, stem cell therapy is a potential strategy regenerating myocardium 2 .…”

Section: Introductionmentioning

confidence: 99%

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

et al. 2017

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Background Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post myocardial infarction (MI). C1q/tumor necrosis factor–related protein-9 (CTRP9) is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. Methods Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were employed to uncover the molecular mechanisms of CTRP9. Results Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 vs. CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling and promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the above noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. Conclusion We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK/MMP-9 and ERK/Nrf2 signaling, and upregulation/secretion of anti-oxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

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“…We have identified a novel stem cell population, isolated from cortical bone, and have shown that these cells have cardio-protective features, both in vitro 28 and in vivo 29 . Cortical bone stem cells (CBSCs) were found to be distinct from cardiac–derived stem cells (CDCs) and mesenchymal stem cells (MSCs), and they possess characteristics that account for their in vivo cardio–protective features 28 .…”

Section: Introductionmentioning

confidence: 99%

Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction

Sharp

Schena

Hobby

et al. 2017

Circulation Research

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Rationale Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. Objective To determine if post–MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. Methods and Results Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia–reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n = 9) (2×107 cells total) or placebo (vehicle; VEH, n = 9) through NOGA® guided transendocardial injections. 5–ethynyl–2’deoxyuridine (EdU), a thymidine analog, containing minipumps were inserted at the time of MI induction. At 72hrs (n=8) initial injury and cell retention were assessed. At 3 Months post–MI, cardiac structure and function was evaluated by serial echocardiography, and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72hrs post–MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC–treated hearts had significantly reduced scar size, smaller myocytes and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular (LV) volumes and ejection fraction were significantly more preserved in CBSC–treated hearts and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU+ cardiac myocytes was increased in CBSC– vs. VEH– treated animals. Conclusions CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves LV functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction (HFrEF).

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Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Cited by 30 publications

References 41 publications

Empowering Adult Stem Cells for Myocardial Regeneration V2.0

Empowering Adult Stem Cells for Myocardial Regeneration V2.0

C1q/Tumor Necrosis Factor–Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction

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