1. After undergoing a transient myocardial infarction (MI), primates injected with stem cells showed improved heart function.
2. None of the primates that received the stem cells developed a tumor from these cells or experienced immune rejection, demonstrating the treatment’s potential safety.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Heart attacks, or MIs, can lead to irreversible heart damage, impairing the heart’s ability to adequately supply oxygen to all of the body’s tissues. Due to the inability of cardiomyocytes to effectively regenerate following a severe MI, the only current effective treatment is to perform a heart transplant. This study investigated transplanting stem cells, cells able to differentiate into cardiomyocytes and self-renew, as a method to improve cardiac function post-MI or following other serious cardiac injuries.
In monkeys, MHC-matched induced pluripotent stem cells (iPSCs) were injected into the infarct and border zone of the induced MI. First, the immune response following this injection was assessed to determine whether the monkeys accepted this transplant. After 12 weeks, there was no evidence of acute graft rejection. The function of these transplanted cells was then tested to determine their contractibility. The monkeys that received the stem cell transplant demonstrated increased heart contractile function post-MI. Finally, after a few months, none of the iPSC-transplanted monkeys demonstrated sustained ventricular tachycardia, a symptom seen post-MI.
A longer observation period will be needed in order to determine the long-term immune effects of this treatment. In addition, other studies will be needed in order to determine the proper procedure for a successful transplant in humans. However, this groundbreaking data demonstrate the potential use of stem cells for cardiomyocyte regeneration.
In-Depth [animal study]: Filipino cynomolgus monkeys were used as donors of iPSCs derived from fibroblasts as well as recipients of the transplanted cells. A fluorescent calcium indicator was developed and transfected into the iPSCs in order to visualize them following transplantation. In vivo, these cells demonstrated spontaneous beating, inhibition with calcium channel inhibitors, and activation following caffeine administration, demonstrating the functional similarities of the transplanted cells to typical cardiomyocytes.
To test the efficacy of a stem cell transplant following cardiac injury, 5 monkeys underwent induced myocardial ischemia for 3 hours followed by reperfusion. They were then immunocompromised by treatment with methylprednisolone and tacrolimus, and 2 weeks later were injected with 4 x 108 cardiomyocyte differentiated iPSCs (iPSC-CMs) that were MHC-matched. No tumor growth was noted at 12 weeks following the implantation, demonstrating the potential safety of these cells and decreased concern of hyper-proliferation. Fluorescent microscopy determined that the structure of the iPSC-CMs was similar to typical cardiomyocytes, and immunohistochemical staining demonstrated a lack of immune infiltration in the grafted area. The lack of immune cells showed that the graft was not rejected.
Finally, micro-computed tomography and echocardiography were used to evaluate the contractile abilities of the heart following transplantation. The ejection fraction was found to be significantly higher in the iPSC-CM treated monkeys after 12 weeks (p>0.01). In addition, none of the animals that received the stem cells experienced sustained ventricular tachycardia at 8 or 12 weeks, demonstrating heart recovery post-MI.
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