Hematopoietic potential of stem cells isolated from murine skeletal muscle

Abstract

We have discovered that cells derived from the skeletal muscle of adult mice contain a remarkable capacity for hematopoietic differentiation. Cells prepared from muscle by enzymatic digestion and 5-day in vitro culture were harvested, and 18 ؋ 10 3 cells were introduced into each of six lethally irradiated recipients together with 200 ؋ 10 3 distinguishable whole bone marrow cells. After 6 or 12 weeks, all recipients showed high-level engraftment of muscle-derived cells representing all major adult blood lineages. The mean total contribution of muscle cell progeny to peripheral blood was 56 ؎ 20% (SD), indicating that the cultured muscle cells generated approximately 10-to 14-fold more hematopoietic activity than whole bone marrow. When bone marrow from one mouse was harvested and transplanted into secondary recipients, all recipients showed high-level multilineage engraftment (mean 40%), establishing the extremely primitive nature of these stem cells. We also show that muscle contains a population of cells with several characteristics of bone marrow-derived hematopoietic stem cells, including high efflux of the fluorescent dye Hoechst 33342 and expression of the stem cell antigens Sca-1 and c-Kit, although the cells lack the hematopoietic marker CD45. We propose that this population accounts for the hematopoietic activity generated by cultured skeletal muscle. These putative stem cells may be identical to muscle satellite cells, some of which lack myogenic regulators and could be expected to respond to hematopoietic signals. Regenerative stem cells can be found in many adult tissues (1-6). Although possessing substantial capacity to proliferate and differentiate, such cells are thought to be committed to differentiate exclusively into the tissues in which they reside. However, recent reports have suggested that some ostensibly tissue-specific progenitors may have differentiation potential outside of their tissue of origin. Ferrari et al. (7) found that lacZ-marked cells derived from bone marrow of donor mice could be incorporated into regenerating skeletal muscle of recipients. After bone marrow transplantation, donor-derived cells have also been found in multiple nonhematopoietic tissues, including liver (8), vascular endothelial cells (9), astroglia in the brain (10), skeletal muscle (7, 11), and bone (12). Although bone marrow contains many cell types that could account for this variety of activities, it is possible that hematopoietic stem cells (HSC) are directly or indirectly involved.Moreover, stem cells derived from nonhematopoietic tissue have been found to differentiate into hematopoietic cells. Bjornson et al. (13) showed that clonal populations of neural stem cells could repopulate the hematopoietic system after bone marrow transplantation. Together, these studies suggest that stem cells derived from adult tissues may retain a previously unrecognized degree of plasticity in their commitment and that their differentiation may be influenced more by environment than by lineage.This possibility led us t...

Muscle-derived cell-mediated ex vivo gene therapy for urological dysfunction

“…Furthermore, recent studies have reported that these cells may exist in skeletal muscle. 7,9,[23][24][25][26][27][28][29] The presence of stem cells in skeletal muscle makes this tissue an attractive source of cells that are capable of enhancing the healing of various tissues. 9 In fact, we have recently observed that the genetic engineering of MDC (mc13) to express rhBMP-2 can be used to enhance closure of a non-healing skull defect.…”

“…23 It is now well established that muscle satellite cells are heterogenous and that skeletal muscle tissue may be a source for pluripotent stem cells. 7,9,[24][25][26][27][28][29] In particular, stem cell populations from muscle were recently shown to reconstitute the hematopoietic compartment of lethally irradiated mice and to partially restore the expression of dystrophin in the mdx mouse, an animal model of Duchenne muscular dystrophy. 7 In our laboratory, we have shown that the population of MDC (pp6) was, in fact, multipotent and had the capability of differentiating into other mesenchymal tissues, such as osteogenic lineage.…”

Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors

“…For example, reserve stem cells derived from bone marrow can differentiate into neurons and glia (Eglitis and Mezey, 1997;Kopen et al, 1999), restore dystrophin expression in skeletal muscle (Gussoni et al, 1999), serve as a source of hepatic oval cells (Petersen et al, 1999), provide cells for neovascularization (Asahara et al, 1999;Kalka et al, 2000), and restore cartilage, bone, and fat (Pittenger et al, 1999;Prokop, 1997;Yoo et al, 1998). Conversely, stem cells derived from neural tissues (Bjornson et al, 1999) and muscle tissues (Jackson et al, 1999) can differentiate into blood. Furthermore, reserve stem cells derived from dermis can differentiate into skeletal muscle, fat, cartilage and bone (Young et al, 1999).…”

A novel role for proteomics in the discovery of cell‐surface markers on stem cells: Scratching the surface

“…these cells could be coaxed to differentiate into cells not normally associated with their 'committed' state) [12]. Examples include HSC that reputedly develop into neural, myogenic and hepatic cell types; neural or skeletal muscle stem cells that develop into the hematopoietic lineage [12][13][14][15][16][17][18]; and stromal stem cells that differentiated into cardiac muscle cells (myocytes) [19]. The reputed trans-differentiation potential and increased developmental potential of most of these adult stem cells has, however, been challenged [20][21][22][23].…”