Skeletal Muscle Regeneration from Embryonic Stem Cells:
Little progress has been made towards the generation of skeletal muscle progenitors from ES cells. This is due to the paucity of paraxial mesoderm formation during EB differentiation and to the lack of reliable identification and isolation criteria for skeletal muscle precursors. We are studying the potential of different myogenic regulatory factors to drive myogenesis from ES cells, and developing methods of purifying myogenic precursors. Inducible Pax3 expression enhances paraxial mesoderm, and allows skeletal myogenic precursors to be expanded from EB cultures. When transplanted into dystrophic mice, Pax3-induced cells demonstrate an exceptional potential for skeletal muscle regeneration, differentiating robustly into adult myofibers. Our focus now is to functionally evaluate the regenerative potential of ES/Pax3-derived myogenic precursors, and to understand the mechanism underlying their generation within paraxial mesoderm during ES/EB differentiation. We also plan to expand these studies to human ES cells.
The Role of Endoglin in Hemangioblast and Early Hematopoietic Development:
The hematopoietic and endothelial lineages arise in mesoderm from a common bipotent progenitor - the hemangioblast. Although an in vitro assay exists for the hemangioblast, very little is known about its regulation. In our search for hemangioblast regulatory molecules, we have discovered that endoglin, an ancillary receptor for several members of the TGF-beta superfamily, plays a critical role in hemangioblast specification. My lab is using endoglin knockout and inducible ES cells to dissect the mechanism underlying endoglin¿s function. We are also investigating the cascade of components associated with TGF-beta signaling (Smads and ALKs) biochemically and genetically.
Origins of Endothelial Progenitors in Adult Hematopoietic Tissues and Therapeutic Applications:
Bone marrow and peripheral blood from adults have been described as rich sources of endothelial progenitor cells. However, it is still not clear which cell type in these heterogeneous tissues might be preferable for vascular regeneration since studies directly comparing different cell sub-populations are lacking. By combining sub-fractionation of cord blood with a clonogenic Blast-CFC assay, we have identified an adult equivalent of the embryonic hemangioblast, which is the likely source of endothelial progenitors in hematopoietic tissues. We are currently investigating the differentiation capacity of this adult bipotent precursor as well as its potential to recover the stem cell niche in degenerative disorders.
Recent Publications:
1. Darabi R, Gehlbach K, Stull JT, Kamm KE, Kyba M & Perlingeiro RCR, (2008) “Functional skeletal muscle regeneration from differentiating embryonic stem cells” Nature Medicine, 14:134-143.
2- Gang EJ, Bosnakovski D, Simsek T, To K & Perlingeiro RCR, (2008) “Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage” Experimental Cell Research, 314:1721-1733.
3. Perlingeiro RCR, (2007) “Endoglin is required for hemangioblast and early hematopoietic development” Development, 134:3041-3048.
4. Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW & Perlingeiro RCR, (2007) “SSEA-4 identifies mesenchymal stem cells from bone marrow” Blood, 109:1743-1751.
5. Perlingeiro RCR, Kyba M, Bodie S & Daley GQ, (2003) “A role for TPO in hemangioblast development” Stem Cells, 21:272-280
6. Kyba M, Perlingeiro RCR & Daley GQ, (2002) “HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors” Cell, 109:29-37
7. Perlingeiro RCR, Kyba M, & Daley GQ, (2001) “Clonal analyis of differentiating embryonic stem cells reveals a hematopoietic progenitor with primitive erythroid and adult lymphoid-myeloid potential” Development, 128:4597-4604
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