What are stem cells?
Stem cells are biological cells that have the ability to differentiate into other types of cells, given the appropriate signals. There are several types of stem cells, including induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and adult stem cells. Adult stem cells are found within most tissues of a human adult, but are multipotent (able to give rise to only a certain subset of cells) and have limited proliferative abilities [1]. ESCs are derived from the inner cell mass of fetal blastula and are pluripotent (able to give rise to any terminal cell type). Induced pluripotent stem cells are stem cells that have been generated from adult somatic cells, and can be patient-specific [2].
Adult stem cells may be found in stem cell niches, which contain a unique microenvironment that permits the stem cells to retain their undifferentiated state [3]. Importantly, the stem cell niches are also located such that the stem cells may receive growth signals from supporting cells. If cells die, stem cells from the stem cell niche may be activated to proliferate, and differentiate, in order to replace the dead cells [4]. For a long time, the cardiac muscle had been thought of as a static organ, but now there is evidence for multipotent stem cell compartments in cardiac tissues as well [5]. These cardiac stem cells (CSCs) are responsible for tissue homeostasis and repair following injury, slowly replacing cardiomyocytes as they die. Widespread cell death, such as what happens in the case of myocardial infarction, requires significant replacement of dead cells.
Stem cells for rebuilding cardiac tissue
In the case of myocardial infarction, not only is there an absence of adequate functional cardiomyocyte replenishment, but there is also fibrotic scar formation at the affected site [2]. In order to compensate for the loss of functional cardiomyocytes that occurs during a cardiac infarction or similar trauma, regenerative therapies are being sought. One promising therapeutic approach involves the use of stem cells to ultimately replace fibrotic scar tissue with functional cardiomyocytes. Therapeutically, regenerative strategies have included stem cell transplantation, cell reprogramming, and stimulating cell proliferation of different cell types in situ. Different stem cell routes for tissue regeneration are described in more detail below…
Dedifferentiation: This describes a terminally differentiated cell reverting back to a less-differentiated stage within its own lineage. From the dedifferentiated stage, the cell can then proliferate again before redifferentiating, replacing cells that were lost. For example, see the following figure from Jopling, et al., 2011 [7]:
This figure depicts the regenerative processes that occur in zebrafish following partial amputation of a cardiac ventricle. During dedifferentiation, the genes for contractile proteins such as ventricular myosin heavy chain (vhmc) are downregulated, and the cells begin to express positive regulators of the cell cycle, which indicate cell proliferation [7]. The fully-differentiated cardiomyocytes have limited proliferative capacity, but the dedifferentiation facilitates an increase in the number of cardiac cells, which regenerates the missing tissue. Inducing dedifferentiation seems to be a plausible way to replace cardiomyocytes that are lost, but by itself it may be insufficient to deal with the fibrotic tissue that builds up at the site of cardiac infarction. Being able to generate new cells in vivo with the help of a dedifferentiation process, however, could circumvent the necessity of transplanting cells [7].
Transdifferentiation: This process involves dedifferentiation to an even earlier progenitor state, (to a point where the cell can even switch lineages), thus permitting it to differentiate into an altogether different cell type. To do this, the cells do not need to dedifferentiate all the way back to a pluripotent state. Experimentally, it has even been suggested that it is possible to directly convert one cell type to another without forming any distinct intermediate cell types, but rather by gradually transforming between one cell type and the next, as depicted in the following figure, from Jopling, et al., 2011 [7]:
In the dedifferentiation process on the left, there is a distinct cell type intermediate between the initial cell type and the final cell type. In the process on the right, there is no distinct intermediate. Transdifferentiation can be done by overexpressing transcription factors or mRNAs, progressively activating the target cell program while suppressing the starting cell’s programs. Since fibroblasts are activated and migrate to the site of a cardiac injury, direct conversion of scar fibroblasts into functioning myocardium would be ideal. Efforts to do this have been made, introducing transcription factors to convert murine fibroblasts into induced cariomyocytes (iCMs) which have spontaneous contraction and action potentials, and express many of the same genes as cardiomyocytes [8], [9]. Functionally, these iCMs may not perform as well as cardiomyocytes, and may exhibit reduced viability. Also, transdifferentiation efficiency can be low. Another standing issue with iCMs is incorporating them into the complex electrophysiological network of the native heart tissue [9].
Direct Reprogramming – Another strategy, quite similar to transdifferentiation, is “direct reprogramming” – where dedifferentiation of an adult somatic cell type proceeds all the way to the cell’s pluripotent beginning (from where it can then differentiate into almost any cell type). This process, induced by transcription factors, was first demonstrated by Takahashi and Yamanaka (2006) [10]. Although generation of iPS cells is possible, directing them into a new lineage is a complex process that can be difficult to control in vivo. It is possible that iPSCs can even give rise to tumors. On the other hand, reprogrammed iPS cells can be genetically modified in vitro, expanded, then incorporated back into the patient.
For more information on stem cells, particularly the use of stem cells for rebuilding cardiac tissue, refer to any of the references below. Ongoing developments in the field may be found on the webpage for the National Center for Regenerative Medicine or on clinicaltrials.gov.
References
[1] L. Barad, R. Schick, N. Zeevi-Levin, J. Itskovitz-Eldor, and O. Binah, “Human Embryonic Stem Cells vs Human Induced Pluripotent Stem Cells for Cardiac Repair,” Can. J. Cardiol., vol. 30, no. 11, pp. 1279–1287, 2014.
[2] W. W.T., S. N., C. J.P., W. T. Wong, N. Sayed, and J. P. Cooke, “Induced pluripotent stem cells: how they will change the practice of cardiovascular medicine,” Methodist Debakey Cardiovasc. J., vol. 9, no. 4, pp. 206–209, 2013.
[3] E. Fuchs and V. Horsley, “Ferreting out stem cells from their niches.,” Nat. Cell Biol., vol. 13, no. 5, pp. 513–518, May 2011.
[4] A. Wabik and P. H. Jones, “Switching roles: the functional plasticity of adult tissue stem cells.,” EMBO J., vol. 34, no. 9, pp. 1164–79, 2015.
[5] P. Anversa, J. Kajstura, M. Rota, and A. Leri, “Regenerating new heart with stem cells,” J. Clin. Invest., vol. 123, no. 1, pp. 62–70, 2013.
[6] L. Qian and D. Srivastava, “Direct cardiac reprogramming: from developmental biology to cardiac regeneration.,” Circ. Res., vol. 113, no. 7, pp. 915–921, Sep. 2013.
[7] C. Jopling, S. Boue, and J. C. Izpisua Belmonte, “Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration.,” Nat. Rev. Mol. Cell Biol., vol. 12, no. 2, pp. 79–89, 2011.
[8] M. Ieda et al., “Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors,” Cell, vol. 142, no. 3, pp. 375–386, Oct. 2016.
[9] S. A. Doppler, M. A. Deutsch, R. Lange, and M. Krane, “Direct reprogramming—The future of cardiac regeneration?,” Int. J. Mol. Sci., vol. 16, no. 8, pp. 17368–17393, 2015.
[10] K. Takahashi and S. Yamanaka, “Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006.
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