From Bone Marrow to Cardiac Atrial Appendage Stem Cells for Cardiac Repair: A Review

Abstract

Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells - CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%).

Combining stem cells in myocardial infarction: The road to superior repair?

“…105,106 The only convincing strategy for clinically relevant cardiomyocyte differentiation requires substantial and direct epigenetic manipulation of BM-MSCs. [107][108][109] Therefore, it is assumed that in a normal physiological environment this type of stem cells can only rarely differentiate into functional cardiomyocytes.…”

“…Nevertheless, other important features of mature cardiomyocytes such as the generation of adult ventricular action potentials, specific ionic currents and the presence of gap junction proteins are not present in these cells 105,106 . The only convincing strategy for clinically relevant cardiomyocyte differentiation requires substantial and direct epigenetic manipulation of BM‐MSCs 107–109 . Therefore, it is assumed that in a normal physiological environment this type of stem cells can only rarely differentiate into functional cardiomyocytes.…”

Hydrogels with Reversible Crosslinks for Improved Localised Stem Cell Retention: A Review

“…iPSCs originate from adult cells but are manipulated to gain similar differentiation abilities to ESCs. For decades researchers have been looking into specific stem cell populations [1] (e. g., iPSCs, [2][3][4][5][6][7] bone marrow-derived stem cells, [8][9][10][11][12] adipose tissue-derived stem cells, [13][14][15] dental pulp stem cells, [16][17][18] cardiac atrial appendage stem cells, [19][20][21][22] etc.) to regenerate tissues.…”

Endothelial and smooth muscle cells derived from human cardiac explants demonstrate angiogenic potential and suitable for design of cell-containing vascular grafts

“…The atrial appendage is traditionally used as a source of c-kit-positive cardiac stem cells [39, 40]. Additionally, in cultures derived from the atrial appendage, the presence of EC and SMC markers has been shown previously [41].…”