Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

Abstract

Objectives To quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods using Positron Emission Tomography (PET). Background Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. Methods CDCs derived from syngeneic, male Wistar Kyoto (WK) rats were labeled with 18FDG and injected intramyocardially into the ischemic region of female WK rats following permanent left coronary artery ligation. The effects of fibrin glue, bradycardia (adenosine) and cardiac arrest were examined. 18FDG PET was performed for quantification of cell retention. Quantitative PCR for the male-specific SRY gene was performed to validate the PET results. Results Myocardial retention of cells suspended in PBS 1 hr after delivery was 17.6±11.5% by PCR and 17.8±7.3% by PET. When CDCs were injected immediately following induction of cardiac arrest, retention was increased to 75.6±18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4±5.3%). A similar increase in CDC retention was observed following epicardial application of fibrin glue at the injection site (37.5±8.2%). PCR revealed a significant increase in 3 week cell engraftment in the fibrin glue animals (22.1±18.6% vs 5.3±3.1%, for fibrin glue and PBS respectively). Conclusions In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with fibrin glue or lowering ventricular rate by adenosine may be clinically translatable methods for improving stem cell engraftment in a beating heart.

The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function

“…Remarkable progress has been made towards the design of biomaterials that promote tissue repair and regeneration [5,7]. In recent years, it has become possible to design smart, multifunctional structures that provide bioactive signaling factors that interact with the surrounding tissue environment to facilitate tissue repair and salvage [8,24].…”

“…Combining bioactive materials with stem cell products represents a natural extension of these approaches given recent meta-analyses demonstrating only modest persistence of injected stem cell products alone (approx. 1-2%) beyond 12 months [5,12,25,26]. As such, a variety of biomaterials have entered active development with the intent of providing a supportive scaffold that improves both acute cell retention and long-term cell viability [8,13,27].…”

“…When compared to other biomaterial-based approaches, cell encapsulation avoids delivery of exogenous pro-thrombotic materials (e.g., delivery of excess exogenous collagen [8] or fibrin glue plugging of the injection site) [5], intrinsic modification of the CSCs (e.g., magnet-based retention of iron labeled CSCs) [7,28] or intracoronary implant of pro-thrombotic metal stents [29]. Importantly, cell encapsulation restricts the use of foreign materials resulting in a significantly lower biomaterial to cell ratio that is gelled prior to transplantation and remains gelled at physiological temperature for straightforward clearance following the integration of CSCs into the myocardium.…”

“…Recently, transplantation of ex vivo proliferated cardiac stem cells (CSC) has garnered attention as a promising means of improving left ventricle function while reducing infarct size [2,3]. Despite these developments, the full capacity of CSCs to repair myocardium is limited by modest retention immediately after transplant into the vascular heart which, in part results in very low long term survival [4,5]. This notion is supported by several recent papers demonstrating early CSC engraftment predicts later cardiac recovery from myocardial infarction while methods targeted towards boosting the early retention of transplanted cells enhance cells-mediated cardiac repair [6][7][8][9].…”

578 Human Blood and Cardiac Stem Cells Synergize to Enhance Cardiac Repair When Co-Transplanted Into Ischemic Myocardium

“…6,7 But despite clear evidence of benefit after cell transplantation, long-term retention of cells is modest (<5% at 3 weeks), regardless of persistent functional benefits. 8 These data hint that a sizable portion of myocardial repair is mediated by paracrine stimulation of endogenous repair or myocardial salvage mechanisms. 9 Although both CAC and CSC transplantation provide myocardial repair, speculation remains as to which cell source is superior.…”