Re: Letter to the Editor on: “Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells.”

Dear Editor,

Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells

We appreciate the thoughtful remarks by Tokmakidis et al. [1] regarding the use of circulating angiogenic cell (CAC) and endothelial progenitor cell (EPC) nomenclature in our recent review paper [2]. In this, as well as several of our publications, we acknowledged the fact that there is a lack of consensus in this area, in line with assertions made by others over the past decade [3] [4] [5]. As outlined in previous reviews from our group [2] [6] [7], it is not our intention to replace the term EPC with CAC. Rather, we decided to use the term CAC as an umbrella term that recognizes the heterogenous mixture of circulating stem, progenitor, hematopoietic and endothelial cells contributing to angiogenesis as noted in Table 1 of our publication. Given this rationale, our definition of CACs is not limited to EPCs, but EPCs would certainly be included as one type of CAC. We direct readers to our previous reviews for an extended explanation [6] [7].

We very much agree with Tokmakidis et al. that there should be a goal to identify the distinct type and function of each cell released and stimulated by muscular exercise. This is why we chose to explicitly describe the cells from each study discussed in our publication based on the cell surface markers and method of isolation that were used. In terms of standardization and transparency, we feel that this is the best approach. In doing so, we did not rename or reclassify cell types from any studies, and instead defined the cell types as they were presented in each respective study. It is worth noting that we also used the term EPC when cell surface markers met the common criteria outlined in Table 1 of our review. Considering this, our best attempts were made to avoid ambiguity.

We do not suggest the use of the term CAC to describe any and all cells that express a marker associated with endothelial repair, and it was not our intent to assign “superiority” to one set of cell surface markers over another or to criticize the previous work of others based on their use of cell surface markers or cell isolation techniques. Instead, we intended to provide readers with current functional data and molecular underpinnings related to the paracrine function of cells falling under the umbrella term of CACs after exercise training. After all, the work presented in our review points to a clear paracrine role of several types of CACs (including EPCs) in promoting angiogenesis, independent of the framework we use to describe them.

In summary, we understand the concerns raised by Tokmakidis et al. and agree that there is a lack of consensus on angiogenic cell nomenclature. This is precisely why we have chosen to adopt the broad term CAC when generally referring to all circulating cells with pro-angiogenic function, but to use cell surface markers and more precise terminology such as EPC when referring to findings from specific populations of cells. At the present time, we believe this to be the most transparent way to present findings and we advocate for use of cell surface markers rather than potentially ambiguous terminology to define cell types of interest both within one’s own work and when referring to the work of others, when possible.

Publication History

Article published online:
03 November 2021

• References

• 1 Tokmakidis SP, Mitsiou G, Smilios I. et al. Letter to the Editor on: “Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells”. Int J Sports Med 2021; 42: 1137–1138
• 2 Evans WS, Sapp RM, Kim KI. et al. Effects of exercise training on the paracrine function of circulating angiogenic cells. Int J Sports Med 2021; 42: 1047-1057
• 3 Richardson MR, Yoder MC. Endothelial progenitor cells: Quo Vadis?. J Mol Cell Cardiol 2011; 50: 266-272
• 4 Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28: 1584-1595.
• 5 Balistreri CR, Buffa S, Pisano C. et al. Are endothelial progenitor cells the real solution for cardiovascular diseases? Focus on Controversies and Perspectives. Biomed Res Int 2015; 2015: 835934
• 6 Witkowski S, Jenkins NT, Hagberg JM. Enhancing treatment for cardiovascular disease: Exercise and circulating angiogenic cells. Exerc Sport Sci Rev 2011; 39: 93-101
• 7 Landers-Ramos RQ, Sapp RM, Shill DD. et al. Exercise and cardiovascular progenitor cells. Compr Physiol 2019; 9: 767-797