1- 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.
2- 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. In this regard, we have been exploiting the potential of adult hemangioblasts to repair the neuronal microenvironment in Amyotrophic Lateral Sclerosis (ALS). The hypothesis underlying this work is that endothelial progenitors preserve or repair the neurogenic niche and slow the course of the disease. An additional benefit of this approach is the generation of wild-type microglia, hematopoietic progeny that maintain the neural microenvironment by scavenging free radicals and reabsorbing decayed tissue. In the SOD mouse model of ALS, adult hemangioblast infusions significantly improve motor neuron function and extend lifespan.
3- 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 myoblasts to be expanded from EB cultures. Upon dox withdrawal, these cells differentiate into muscle in vitro. When transplanted into cardiotoxin-injured immunodeficient or dystrophin-deficient immunosuppressed 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 myoblasts, 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.
RESEARCH INTERESTS
Stem Cell Biology
Muscle Regeneration
Hemangioblast Development
RECENT PUBLICATIONS
Perlingeiro RCR, "Endoglin is required for hemangioblast and early hematopoietic development" Development, 134:3041-3048, July 2007
Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW & Perlingeiro RCR, "SSEA-4 identifies mesenchymal stem cells from bone marrow" Blood, 109:1743-1751, February 2007
Perlingeiro, R.C.R., Kyba, M., Bodie S. and Daley G.Q., "A role for TPO in hemangioblast development" Stem Cells, 21:272-280, 2003
Kyba, M., Perlingeiro, R.C.R., Daley, G.Q., "HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors" Cell, 109:29-37, 2002
Perlingeiro, R.C.R., Kyba, M., Daley, G.Q, "Clonal analysis of differentiating embryonic stem cells reveals a hematopoietic progenitor with primitive erythroid and adult lymphoid-myeloid potential" Development, 128:4597-4604, 2001
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