Stem cells in adult skeletal muscle and other tissues

Until recently, satellite cells were presumed to be the only candidates for the role of stem cells of skeletal muscle. However, multiple groups have demonstrated that stem cells isolated by various techniques either from bone marrow (15,33) or from brain (34,35) can contribute to myotube formation in vitro or to skeletal muscle repair in vivo. The isolation of a highly enriched population of stem cells from various tissues was based on methods that made use of the ability of stem cells to exclude dyes actively, like Rhodamin 123 and Hoechst 33342 (11,36). The population of cells thus isolated (side population, SP) was characterized with astonishing plasticity.

In addition to the above-mentioned examples of myogenic potential of SP cells from bone marrow and brain, it was also shown that skeletal muscle SP cells can contribute to both muscle and hematopoietic compartments in mice (15,16,33), and that unfractionated bone marrow cells can reconstitute the hepatic cell lineage (37) and muscle (33). Strikingly, adult stem cells from brain were reported to repopulate the hematopoietic system of lethally irradiated recipients (38). However, this last result was not reproducible with primary neural stem cells and awaits further investigation (39).

Fig. 2. Hypotheses concerning the origin of adult stem cells. (A) Stem cells develop from common primitive precursor (possibly hematopoietic stem cell [HSC]), are trapped in various tissues during embryogenesis or early postnatal stages, and are committed to those tissues by local signals. This theory suggests a certain level of determination of adult stem cells and does not explain their plasticity. (B) Stem cells can be recruited to different organs and tissues by specific signaling molecules. In the absence of such signals, the yet-unidentified precursors of stem cells form part of the blood vessel system.

Fig. 2. Hypotheses concerning the origin of adult stem cells. (A) Stem cells develop from common primitive precursor (possibly hematopoietic stem cell [HSC]), are trapped in various tissues during embryogenesis or early postnatal stages, and are committed to those tissues by local signals. This theory suggests a certain level of determination of adult stem cells and does not explain their plasticity. (B) Stem cells can be recruited to different organs and tissues by specific signaling molecules. In the absence of such signals, the yet-unidentified precursors of stem cells form part of the blood vessel system.

These unexpected findings seriously challenged the classical views of the tissue-restricted fate of stem cells. Therefore, it is very important to raise the issue of possible heterogeneity within the enriched populations of SP cells from various tissues. Indeed, heterogeneity has been reported in the hematopoietic stem cell population (40), and it is presently not known whether fate changes of somatic stem cells reflect the ability of a presently undefined subtraction of a given stem cell population.

The possible solution to the problem of heterogeneity of SP cells, or stem cells from various tissues, is the determination of surface-specific markers characteristic for each stem cell type. This approach, combined with functional assays, will gradually allow the isolation of stem cells with great precision and homogeneity. Given that the plasticity of SP from different tissue types will be confirmed for purified stem cells, how can this plasticity be explained?

One explanation is the existence of one type of primitive stem cell that penetrates all tissue types, perhaps during development, but preserves its pluripotential characteristics (41) (Fig. 2A). A variation of this hypothesis is to presume the existence of a number of such stem cell subtypes, each with a potential to contribute to some, but not all, lineages (neurohematopoietic, neuromuscular stem cells).

Another, quite different, explanation is to hypothesize that some cells in an adult organism can be recruited to different tissue types by certain chemokines and signal transduction proteins, but in the absence of such signals, they form part of another tissue (Fig. 2B). Obvious and logical candidates for this role will be cells that form the blood vessels (42). Indeed, as a pluripotent SP cell fraction has been described for multiple tissue types, common features, such as the presence of a network of capillaries, might be explored for these tissue types. Developing blood vessels will be the origin of this common progenitor, an adult "mesohemangioblast."

This hypothesis is partially supported by the study of De Angelis et al. (28), which demonstrated the participation of aorta-derived myogenic progenitors in muscle regeneration. Interestingly, another group of researchers showed that bone marrow-derived hematopoietic stem cells can form smooth muscle cells that contribute to arterial remodeling in vivo (43). This result presents another example of developmental plasticity of adult stem cells and especially the extraordinary plasticity observed between hematopoietic and muscle tissue.

Satellite cells of skeletal muscle coexpress myogenic and endothelial markers, further suggesting that at least some adult stem cells might be derived from vascular lineage. However, the exact identity of these hypothetical blood vessel-based pluripotent precursor cells remains to be established.

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