Welcome to the Kyba Lab

Lineage-specific stem cells from ES/iPS cells.

The ability to reprogram somatic cells to the pluripotent state has opened up new possibilities for cell therapy.  We are studying the regulatory pathways that give rise to three specific lineages within mesoderm: blood, cardiac, and skeletal muscle, with the goal of applying this knowledge to the generation of therapeutic lineage-restricted stem cells suitable for regenerative medicine. 

The Hox code for hematopoietic stem cell self-renewal.

Gain of function studies with HoxB4 have shown that this Hox family member is involved in the regulation of self-renewal.  Unfortunately, because other Hox genes cause leukemia when constitutively expressed, they have largely been ignored.  By using conditional gene expression, we have shown that HoxB4 is neither unique in promoting hematopoietic stem cell self-renewal, nor most potent.  We wish to understand how Hox genes control stem cell self-renewal, and are identifying regulatory circuits under Hox control. 

Lineage-specific reprogramming of somatic cells.

 The use of 4 transcription factors to convert somatic cells into pluripotent cells, together with earlier studies on MyoD-mediated reprogramming of cell fate show that radical intervention in the system for specifying and maintaining cell fate is possible simply by expressing key transcription factors.  We have found a transcription factor cocktail that drives blood development at high efficieny, and are applying this approach towards the goal of generating hematopoietic stem cells directly from somatic cells, bypassing the pluripotent state.

Skeletal muscle stem cells and iPS cells from FSH muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy with a prevalance approaching that Duchenne's, is caused by chromatin changes associated with a contraction of macrosatellite repeats at 4qter.  How these chromatin changes cause disease is not understood.  The macrosatellite repeat encodes a Hox gene named DUX4, with homeodomains similar to those of Pax7.  We have shown that DUX4 and Pax7 can compete for control of expression of myogenic regulators such as MyoD, and are testing the hypothesis that DUX4, expressed in satellite cells, interferes with myogenesis in FSHD-affected muscle.  Because satellite cells are rare and difficult to access, we have generated iPS cells from FSHD patients, and are studying chromatin changes and gene expression at 4qter that occur with the development of the muscle lineage and skeletal muscle stem cells in vitro.

A rotation position is currently open. Students enrolled in a UMN graduate program and interested in pursuing studies on the regulation of blood or muscle stem cells or muscular dystrophy should contact Dr. Kyba by email.

Postdoctoral positions are available. Candidates with an interest in molecular regulation of blood, cardiac or skeletal muscle stem cells or the misregulation of muscle stem cells in muscular dystrophy should send a C.V. and contact information for three references to Dr. Kyba by email.

Bosnakovski D, Daughters RS, Xu Z, Slack JMW, Kyba M. (2009) "Biphasic myopathic phenotype of mouse DUX, an ORF within conserved FSHD-related repeats" PLOS One 4:e7003

Ferdous A, Capriolli A, Iacovino M, Martin CM, Morris J, Richardson JA, Latif S, Hammer RE, Harvey RP, Olson EN, Kyba M, Garry DJ. (2009) "Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo" Proc Natl Acad Sci USA 106:814-819

Darabi R, Baik J, Klee M, Kyba M, Tupler R, Perlingeiro RC. (2009) "Engraftment of embryonic stem cell-derived myogenic progenitors in a dominant model of muscular dystrophy" Exp. Neurol. (in press)

Gang EJ, Darabi R, Bosnakovski D, Xu Z, Kamm KE, Kyba M, Perlingeiro RC. (2009) "Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery"

Exp Cell Res. 315:2624-2636.

Iacovino M, Hernandez C, Xu Z, Bajwa G, Prather M, Kyba M. (2009) “A conserved role for Hox paralog group group 4 in regulation of hematopoietic progenitors” Stem Cells Dev. 18:783-792.

Bosnakovski D, Xu Z, Gang EJ, Galindo CL, Liu M, Simsek T, Garner HR, Agha-Mohammadi S, Tassin A, Frédérique Coppée, Belayew A, Perlingeiro RCR, Kyba M (2008) "An isogenetic myoblast screen identifies DUX4-mediated FSHD-associated molecular pathologies" EMBO J. 27:2766-2779.

Tang W, Zeve D, Suh J, Bosnakovski D, Kyba M, Hammer B, Tallquist MD, Graff JM. (2008) "White fat progenitor cells reside in the Adipose Vasculature" Science 322:583-536.

Bosnakovski D, Xu Z, Li W, Thet S, Cleaver O, Perlingeiro RCR, Kyba M (2008) "Prospective isolation of skeletal muscle stem cells with a Pax7 reporter" Stem Cells 26:3194-3204.

Ismailoglu, I, Yeamans G, Daley GQ, Perlingeiro RCR, Kyba M, (2008) "Mesodermal patterning activity of SCL" Exp. Hematol. 36:1593-1603.

Bosnakovski, D, Lamb S, Simsek T, Xu Z, Belayew A, Perlingeiro R, Kyba M, (2008) "DUX4c, an FSHD candidate gene, interferes with myogenic regulators and abolishes myoblast differentiation" Exp. Neurol. 214:87-96.

Bondue, A, Lapouge G, Paulissen C, Semeraro C, Iacovino M, Kyba M, Blanpain C. (2008) "Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification" Cell Stem Cell 3:69-84.

Lindsley, RC, Gill JG, Murphy TL, Langer EM, Cai M, Mashayekhi M, Wang W, Niwa N, Nerbonne JM, Kyba M, Murphy KM. (2008) "Mesp1 coordinately regulates cardiovascular fate restriction and epithelial-mesenchymal transition in differentiating ESCs" Cell Stem Cell 3:55-68.

Fujita, J, Crane, AM, Souza, MK, Dejosez, M, Kyba, M, Flavell, RA, Thomson, JA, Zwaka, TP (2008) "Caspase activity mediates the differentiation of embryonic stem cells" Cell Stem Cell 2:595-601.

Lee D, Park C, Lee H, Lugus JJ, Kim SH, Arentson E, Chung YS, Gomez G, Kyba M, Lin S, Janknecht R, Lim DS, Choi K. (2008) "ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification" Cell Stem Cell 2:497-507.

Darabi, R, Gelbach, K, Bachoo, RM, Kamath, S, Osawa, M, Kamm, KE, Kyba M, Perlingeiro, RCR. (2008) "Functional skeletal muscle regeneration from differentiating embryonic stem cells" Nature Medicine 14:134-143.