A significant number of clinical cardiologists have been pursuing the use of various progenitor / precursor / pluripotent cell types to heal / recover / restore damaged and infarcted myocardium. Unlike the methods focusing on implanting cardiomyocytes following in vitro differentiation, a competing school of thought is attempting to inject progenitor cells into the blood stream. For the latter approach, there are a series of steps presumed for efficacy to be demonstrated. The general premise is that the precursor cells, one in the bloodstream, will:
Step 1. Migrate to the vessel proximal to the area of the injury
Step 2. Travel through the layers of the vasculature
Step 3. Migrate further to the specific area of ischemic / stunned / infarcted myocardium
Step 4. Accept unique local signaling cues to differentiate into mature myocardium
Step 5. (Optional) Secrete signaling cues to mobilize resident precursor cells to differentiate and ameliorate the damaged area
In the clinic, bone marrow-derived mononuclear cells used in this manner flopped spectacularly (1), although various efforts (C-Cure from Cardio3 to Capricore’s CDCs) continue to use populations of precursor cells that are expected to complete Steps 1 through 5 in order to achieve efficacy. Generally, I’m highly skeptical of these latter methods for various reasons. There are limited to data to describe the signaling that controls Step 1. Further, it is unclear how these precursor cells, which are not expected to be migratory, are able to travel through the layers of endothelium to exit the lumen of the vessels and capillaries that they’re in. For example, leukocytes have specific mechanisms that dictate their adhesion to, and migration out, of vessels at specific sites (2). For proponents of precursor-based myocardial repair, no meaningful mechanisms are provided to explain the mode of migration used to exit the blood stream. The limitations of Step 3 overlap with Step 1, and presumably a solution for the latter will apply to the former. The localized signaling cues required to achieve Step 4 largely remain mysterious in the context of cells injected into the blood stream.
Step 5 is similarly ambiguous. A recent paper by Tomasetti and Vogelstein (3) presents a significant challenge to the assumptions behind Step 5. In the paper, the authors test a possible link between organ-specific cancer risk and the effects associated with lifetime number of stem cell divisions (Figure 1, which can be seen at the following link). The note a correlation of 0.81 between lifetime risk and total stem cell divisions. So how does a figure linking lifetime cancer risk to total stem cell divisions relate at all to healing the heart?
One of the clues may be apparent in what Tomasetti and Vogelstein do not show: the heart is absent in their figure. The reason is largely because the heart is not a hot spot for cancers. Myxomas may be readily prevalent in some people with Carney’s complex (4), but there is a strong genetic basis related to endocrine overactivity and modulated cAMP-dependent protein kinase function. So if the prevalence of cancer is low, what about the regenerative capacity of the heart?
Generally speaking, the heart is not remarkable for its regenerative capacity. A recent paper noted that a subpopulation of c-Kit expressing cells in the heart may produce new cardiomyocytes, comprising up to 0.016% when stimulated by injury (5). Yes, 0.016%. This finding should not be too surprising. Regeneration in the heart, despite the hopes and desires of some, has always been very low. Even further, an interesting study from 2009 suggested that cardiomyocytes renew at ~1% annually until the age of 25, and then decline to ~0.5% by the age of 75 (6).
Interestingly, the lack of regenerative capacity in the heart is very much at odds with companies that are publicizing a pipeline product that hopes to capitalize on this inherent regenerative capacity. In effect, acceptance that such a regenerative capacity may be insignificant is a considerable challenge to these programs. In that respect, I think the paper by Tomasetti and Vogelstein adds yet another nail to the coffin of the “heart-is-a-regenerative-organ” proponents. If the heart is readily regenerative, lifetime total stem cell divisions would be higher *and* the lifetime risk of neoplasia would be higher… or at least figure measurably in Tomasetti and Vogelstein’s data.
At this point, methodologies claiming to utilize the inherent regenerative capacity of the heart are based more on data-free optimism than a rational view of the literature.