Early Stem Cell Engraftment Predicts Late Cardiac Functional Recovery

Abstract

Background Human cardiac progenitor cells have demonstrated great potential for myocardial repair in small and large animals, but robust methods for longitudinal assessment of their engraftment in humans is not yet readily available. In this study, we sought to optimize and evaluate the use of positron emission tomography (PET) reporter gene imaging for monitoring human cardiac progenitor cell (hCPC) transplantation in a mouse model of myocardial infarction. Methods & Results hCPCs were isolated and expanded from human myocardial samples and stably transduced with variations of the thymidine kinase (TK) PET reporter gene. TK-expressing hCPCs were characterized in vitro and transplanted into murine myocardial infarction models (n=60). Cardiac echocardiographic, magnetic resonance imaging (MRI), and pressure-volume (PV) loop analyses revealed improvement in left ventricular contractile function two weeks after transplant (hCPC vs. PBS, P<0.03). Noninvasive PET imaging was used to track hCPC fate over a four week time period, demonstrating a substantial decline in surviving cells. Importantly, early cell engraftment as assessed by PET was found to predict subsequent functional improvement, implying a “dose-effect” relationship. We isolated the transplanted cells from recipient myocardium by laser capture microdissection for in vivo transcriptome analysis. Our results provide direct evidence that hCPCs augment cardiac function after their transplantation into ischemic myocardium through paracrine secretion of growth factors. Conclusions PET reporter gene imaging can provide important diagnostic and prognostic information regarding the ultimate success of human cardiac progenitor cell treatment for myocardial infarction.

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

“…While direct differentiation into working heart tissue provides a small portion of CSCmediated benefits, emerging evidence suggests that the local production of cardio-protective and pro-angiogenic cytokines plays an important role in the transplant associated outcomes [6,22,23]. To ensure that the production of cytokines was not inhibited in encapsulated CSCs, a representative panel of cytokines was profiled within conditioned media collected under stress conditions (1% oxygen tension and low serum media) from adherent, encapsulated and suspended CSCs.…”

“…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]. These measures address the challenge to acutely retain injected cells within a vascular organ by reducing mechanical extrusion from the myocardium and clearance through lymphatic or venous drainage [10,11].…”

Comparison of Transendocardial and Intracoronary CD34 + Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy

“…8 In patients with ischemic heart failure, transendocardial cell delivery has been shown to be safe and was associated with enhancement of regional and global left ventricular function. 9 Similarly, direct transthoracic IM injection of bone marrow mononuclear cells has been associated with global contractility increment in patients with DCM.…”

Mechanistic molecular imaging of cardiac cell therapy for ischemic heart disease

“…To overcome poor tissue penetration and high background signal, imaging of large animals and humans requires PET/SPECT imaging. For instance, the herpes simplex virus thymidine kinase (HSV-tk) reporter gene labeled with 124 I or 18 F is used for PET imaging (26,48) (Fig. 1), and the human sodium iodide symporter (NIS) reporter gene is used for PET imaging with 124 I as tracer or for SPECT imaging with 99m Tc (72).…”