Dose-dependent systolic contribution of differentiated stem cells in post-infarct ventricular function

Shim, Winston; Tan, Genevieve; Gu, Yacui; Qian, Ling-Bo; Li, Shiqi; Chung, Ying Ying; Lim, Sze Yun; Sim, Eugene K.W.; Chuah, Seng Chye; Wong, Philip

doi:10.1016/j.healun.2010.06.009

Cited by 10 publications

(8 citation statements)

References 32 publications

(19 reference statements)

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“…For instance, intramyocardial injection of escalating doses of human bone marrow-derived CD34 pos cells in rats, 26 human undifferentiated mesenchymal stem cells (MSCs) and differentiated cardiomyocyte-like cells (CLCs) in rats, 27 and human cardiospheres in mice 28 has been reported to impart dose-dependent functional and histological benefits. Intravenous delivery of MSCs in a porcine model of MI has also been reported to produce a dose-dependent beneficial effect on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction

Tang

Rokosh

Sanganalmath

et al. 2015

Circ: Heart Failure

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Background Although c-kitpos cardiac stem cells (CSCs) preserve left ventricular (LV) function and structure after myocardial infarction (MI), CSC doses have been chosen arbitrarily and the dose-effect relationship is unknown. Methods and Results Rats underwent a 90-min coronary occlusion followed by 35 days of reperfusion. Vehicle or CSCs at 5 escalating doses (0.3 ×106, 0.75 ×106, 1.5 ×106, 3.0 ×106, and 6.0 ×106 cells/heart) were given intracoronarily 4 h after reperfusion. The lowest dose (0.3 ×106) had no effect on LV function and morphology, whereas 0.75, 1.5, and 3.0 ×106 significantly improved regional and global LV function (echocardiography and hemodynamic studies). These three doses had similar effects on echocardiographic parameters (infarct wall thickening fraction, LV end-systolic and end-diastolic volumes, LV ejection fraction) and hemodynamic variables (LV end-diastolic pressure, LV dP/dtmax, preload adjusted maximal power, end-systolic elastance, preload recruitable stroke work), and produced similar reductions in apoptosis, scar size, infarct wall thinning, and LV expansion index and similar increases in viable myocardium in the risk region (morphometry). Infusion of 6.0 ×106 CSCs markedly increased post-procedural mortality. GFP and BrdU staining indicated that persistence of donor cells and formation of new myocytes were negligible with all doses. Conclusions Surprisingly, in this rat model of acute MI, the dose-response relationship for intracoronary CSCs is flat. A minimal dose between 0.3 and 0.75 ×106 is necessary for efficacy; above this threshold, a four-fold increase in cell number does not produce greater improvement in LV function or structure. Further increases in cell dose are harmful.

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Section: Discussionmentioning

confidence: 99%

Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction

Tang

Rokosh

Sanganalmath

et al. 2015

Circ: Heart Failure

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“…17 Even though dose-dependent recovery of cardiac function following stem cell transplantation has been demonstrated previously, overall survival of the injected cells remained low. 18 Approaches taken to retain stem cells are likely to be critical to overall functional recovery. Apart from conferring passive mechanical support to the compromised ventricular wall, scaffolding with biocompatible cardiac matrices may precondition stem cells to assimilate more readily into the myocardium.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic Contribution of Stem Cell Scaffolding in Acute Injured Myocardium

Qian

Shim

et al. 2012

Tissue Engineering Part A

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Tissue-engineered scaffolds may improve experimental outcomes in cardiac cell therapy by targeted delivery of stem cells and mechanically support an infarcted left ventricular (LV) wall. We transplanted cardiomyocyte-like cells (5×10(5)) with scaffolding via epicardial patching (cell patch, n=17) or a low-dose intramyocardial hydrogel (LD hydrogel, n=18), a high-dose (5×10(6)) intramyocardial hydrogel (HD hydrogel, n=18) or transplanting a serum-free medium control (control, n=13), a blank patch (n=14), and a blank gel (n=16) for targeted cardiomyoplasty in a myocardial infarcted rat model. LV real-time hemodynamics were assessed using a 1.9-F pressure-volume catheter 7 weeks after stem cell transplantation. All mode of scaffold transplantation protected diastolic function by preserving LV wall integrity that resulted in a lower end diastolic pressure-volume relationship (EDPVR) as compared to a control medium-injected group. Moreover, epicardial patching, but not hydrogel injection, reduced ventricular wall stress with a significantly better LV end diastolic pressure (EDP: 5.3±2.4 mmHg vs. 9.6±6.9 mmHg, p<0.05) as compared to control. Furthermore, epicardial patching additionally preserved systolic function by modulating negative remodeling through restricting dilatation of the LV chamber. In comparison to control, an improved ejection fraction in the cell patch group (80.1%±5.9% vs. 67.9%±3.2%, p<0.01) was corroborated by load-independent enhancement of the end systolic pressure-volume relationship (ESPVR: 0.88±0.61 mmHg/uL vs. 0.29±0.19 mmHg/uL, p<0.05) and preload recruitable stroke work (PRSW: 68.7±26.4 mmHg vs. 15.6±16.2 mmHg, p<0.05) in systolic function. Moreover, the cell patch group (14.2±1.7 cells/high-power field vs. 7.4±1.6 cells/high power field, p<0.05) was significantly better in myocardial retention of transplanted stem cells as compared to the LD hydrogel group. Collectively, myocardial transplantation of compliant scaffolding materials alone may physically improve wall mechanics, largely independent of stem cells. However, epicardially grafted cell patch conferred added systolic contractility by improving stem cell retention and cellular alignment leading to improved LV remodeling and geometric preservation postinfarction.

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“…In comparison to undifferentiated MSCs, CLCs prevented negative remodeling and improved hemodynamic recovery (110). Furthermore, superiority of CLCs over MSCs was demonstrated in load-independent measurements of the end-systolic pressure–volume relationship and preload recruitable stroke work (100). Similarly, Behfar et al (8) demonstrated that guided cells when delivered into infarcted myocardium of nude mice showed superior functional and structural benefits as compared to their unguided counterparts.…”

Section: Differentiated or Undifferentiated Cells For Caridac Repair?mentioning

confidence: 99%

Cardiac Stem Cell Therapy: Stemness or Commitment?

Mehta

Shim

2013

Cell Transplant

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Cardiac stem cell therapy to promote engraftment of de novo beating cardiac muscle cells in cardiomyopathies could potentially improve clinical outcomes for many patients with congestive heart failure. Clinical trials carried out over the last decade for cardiac regeneration have revealed inadequacy of current approaches in cell therapy. Chief among them is the choice of stem cells to achieve the desired outcomes. Initial enthusiasm of adult bone marrow stems cells for myocyte regeneration has largely been relegated to paracrine-driven, donor cell-independent, endogenous cardiac repair. However, true functional restoration in heart failure is likely to require considerable myocyte replacement. In order to match stem cell application to various clinical scenarios, we review the necessity to preprime stem cells towards cardiac fate before myocardial transplantation and if these differentiated stem cells could confer added advantage over current choice of undifferentiated stem cells. We explore differentiation ability of various stem cells to cardiac progenitors/cardiomyocytes and compare their applicability in providing targeted recovery in light of current clinical challenges of cell therapy.

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Dose-dependent systolic contribution of differentiated stem cells in post-infarct ventricular function

Cited by 10 publications

References 32 publications

Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction

Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction

Hemodynamic Contribution of Stem Cell Scaffolding in Acute Injured Myocardium

Cardiac Stem Cell Therapy: Stemness or Commitment?

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