Re: Can hematopoietic stem cells be changed into muscle?

Yes

But for the opposite reason than you suggest - Pax7 prevents differentiation of satellite cells (muscle stem cells) into muscle, so expressing it in any other stem cells would also prevent their differentiation.

Pax7 is a transcription factor [it binds to DNA and controls the expression of other genes] that is a member of the Paired-box family of homeotic [determining tissue identity] genes. Another member of this family, Pax3, is highly homologous to Pax7, and has an overlapping expression pattern that at first suggested that the two factors may share the same role and act in a compensatory fashion. While their relative roles in development have been better disected, their roles in muscle development are still nearly identical: Pax3 and Pax7 prevent pre-myogenic cells in the somites from differentiating into myoblasts prior to their migration out of the somites and into the body wall and limbs (1). While both Pax3 and Pax7 are expressed in the cells of the body wall, only Pax3 is expressed in cells migrating into the limbs, such that mice lacking Pax3 (2) develop normal axial [body wall] musculatures but no appendicular [limb] musculatures (3) - without Pax3 or Pax7, the pre-myogenic cells begin to differentiate before they have a chance to migrate. After migration into the limbs, these pre- myogenic cells switch off Pax3 and begin to differentiate into muscle; however, a small subset of these cells turn on Pax7 instead and become satellite cells. In adults, Pax7 is expressed in undifferentiated satellite cells and inhibits their expression of myogenic transcription factors, such that artifically maintaining the expression of Pax7 in satellite cells - or expressing it in other stem cells - would prevent them from ever becoming muscle. Your confusion most likely comes from the fact that mice deficient in Pax7 do not develop satellite cells (4): since there is no block to differentiation after Pax3 disappears, all of the pre-myogenic precursors develop into muscle, and none are left over to become satellite cells.

The proteins that are responsible for directing cells down the pathway of muscle development are members of the basic, helix-loop-helix (bHLH) family of transcription factors, specifically: MRF4, Myf5, myogenin, and Myo-D, in order of expression. Although loss of at least three of these factors is required to prevent muscle development in mice, expression of Myo-D alone is sufficient to cause stem cells to differentiate into muscle (5). In fact - and addressing your original question - expression of Myo-D can cause most non-muscle stem cells to differentiate into muscle, including fibroblasts, neural stem cells (6), and bone-marrow stem cells (7,8). Not only can hematopoietic stem cells from the bone marrow be induced to form muscle by artificially expressing Myo-D, but there is evidence that much of the new muscle tissue developed at sites of injury originates from resident and recruited hematopoietic stem cells rather than from satellite cells; that is, there is a normal, physiological role for the conversion of hematopoietic stem cells into muscle during muscle regeneration. However, it is not Pax7 but rather Myo-D that induces myogenesis.

1. A. G. Borycki, J. Li, F. Jin, C. P. Emerson and J. A. Epstein (1999) Pax3 functions in cell survival and in pax7 regulation, Development 126(8): 1665-1674.

2. Jax® | Mice information card for mouse strain: C57BL/6J-Pax3^Sp/+ (Splotch).

3. P. Tremblay, S. Dietrich, M. Mericskay, F. R. Schubert, Z. Li, and D. Paulin (1998) A Crucial Role for Pax3 in the Development of the Hypaxial Musculature and the Long-Range Migration of Muscle Precursors, Developmental Biology 203(1): 49-61.

4. P. Seale, L. A. Sabourin, A. Girgis-Gabardo, A. Mansouri, P. Gruss, and M. A. Rudnicki (2000) Pax7 Is Required for the Specification of Myogenic Satellite Cells, Cell 102(6): 777–786.

5. A. Asakura, M. A. Rudnicki, and M. Komaki (2001) Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation, Differentiation 68(4-5): 245-253.

6. R. Galli, U. Borello, A. Gritti, M. G. Minasi, C. Bjornson, M. Coletta, M. Mora, M. G. Cusella-De Angelis, R. Fiocco, G. Cossu, and A. L. Vescovi (2000) Skeletal myogenic potential of human and mouse neural stem cells, Nature Neuroscience 3(10): 986 - 991.

7. G. Ferrari, G. Cusella-De Angelis, M. Coletta, E. Paolucci, A. Stornaiuolo, G. Cossu, and F. Mavilio (1998) Muscle Regeneration by Bone Marrow-Derived Myogenic Progenitors, Science 279(5356): 1528-1530.

8. S. L. McKinney-Freeman, K. A. Jackson, F. D. Camargo, G. Ferrari, F. Mavilio, and M. A. Goodell (2002) Muscle-derived hematopoietic stem cells are hematopoietic in origin, Proceedings of the National Academy of Science USA 99(3): 1341-1346.