Contact Information
Assistant Professor of Pathology
Email: kobielakk@keck.usc.edu
Office Phone: 323-442-3208
Lab Phone: 323-442-7831
Fax: 323-442-7832
Lab Location: 1450 Biggy St, NRT- 4516
Office Location: 1450 Biggy St, NRT- 4506
CV: Kobielak CV.pdf
Education
Ph.D. 1999 Biochemistry and Molecular Genetics, Marcinkowski University of Medical Sciences, Poznan, Poland M.D. 1996 Medicine, Marcinkowski University of Medical Sciences, Poznan, Poland
Recent Publications
Kobielak K., Stokes N, de la Cruz, Polak L, Fuchs E. (2007) Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. PNAS 104:10063-10068, 2007
Kobielak K., Pasolli HA., Alonso L., Polak L., Fuchs E. (2003) Defining BMP function in the hair follicle by conditional ablation of BMP receptor-1A. J. Cell Biol. 163:609-623
Kobielak K., Kobielak A., Roszkiewicz J., Wierzba J., Limon J., Trzeciak W.H. (2001) Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia. Am. J. Med. Genet. 100(3):191-7
Kobielak K., Kobielak A., Roszkiewicz J., Limon J., Trzeciak W.H. (2000) Recurrent deletion of the region encoding two (Gly-X-Y) repeats in patients with anhidrotic ectodermal dysplasia indicates an important role for collagen-like domain of the EDA gene product - ectodysplasin A. Pediatric Pathology and Molecular Medicine 19(6):425-432
Research Description
It is known that in adult skin each hair follicle contains a reservoir of stem cells (SCs) localized in the bulge. Within the tissue, SCs reside in niches that provide a specialized environment to regulate their proliferation and then differentiation. Initially I was interested in the role of BMP signaling in development and differentiation of hair progenitors. Using conditional gene targeting in mice and biochemistry in keratinocytes culture, I found that BMP receptor 1A (BMPR1A) is essential for the differentiation of progenitor cells of hair shaft and the inner root sheath. At that time the canonical Wnt signaling pathway was the best characterized where the stabilization of beta-catenin results in activation of the Lef1/Tcf family members in the differentiating cells (cortex) of the developing hair shaft. Although I demonstrated that Lef-1 expression is maintained, its regulatory control of hair shaft differentiation was blocked and BMPRIA null follicles failed to activate canonical Wnt signaling and consequently Lef1/beta-catenin target genes. Moreover, I found that the Wnt-mediated transcriptional activation could be restored by transfecting BMPRIA null keratinocytes with a constitutively active form of beta-catenin. Thus, we were the first group that revealed the cross-talk between BMP and Wnt pathways in hair shaft differentiation and placed the block downstream from Lef1 expression but upstream from beta-catenin stabilization.
My initial observation suggested that without BMP signaling hair follicle stem cell niche does not form properly therefore I decided to focus on the role of BMP signaling in hair follicle niche regulation. Since conditional straight BMPR1A knockout (KO) mice died just after the birth, before the hair follicle stem cell niche was formed I generated an inducible conditional targeting strategy to uncover roles for BMP signaling in hair follicle SCs in adult mice. I found that inhibition of BMP signaling in follicle SCs is essential for promoting the transition between quiescent bulge SCs to proliferating progeny, causing an expansion of the niche and loss of slow-cycling cells. I further showed that although several main features of follicle stem cells are perturbed, namely CD34 and label retention were lost upon Bmpr1a targeting, the SCs are not lost. Since hair follicle maintained ability to repair epidermal wounds which further suggests that multipotent SCs survived Bmpr1a ablation.
Therefore my findings argue that BMPR1A inhibition is essential for the maintenance of proliferating bulge progeny, but that CD34 and label retention are not essential features of follicle SCs. I demonstrated that the key component of BMPR1A-deficient SCs is their elevated levels of both Lef1 and beta-catenin, which are required for initiation of the premature hair cycle. Although beta-catenin can be stabilized by Wnt signaling, I showed that BMPR1A-deficiency enhances beta-catenin stabilization through a pathway involving PTEN inhibition and PI3K/AKT activation. Conversely, sustained BMP signaling in the SC niche blocks activation and promotes premature hair follicle differentiation. Together, my studies revealed the importance of balancing BMP signaling in the SC niche as well as provided a mechanistic link for the convergence of BMP and Wnt pathways in follicle SCs activation. To summarize, my data implicate the canonical BMP pathway in hair follicle differentiation as well as stem cell and stem cell niche regulation, but precisely how BMP signaling functions at the molecular level still remains unknown. Therefore I focus my research to further understand the role of BMP signaling in these three aspects of skin and hair follicle biology, namely: 1) differentiation of hair follicle stem cells/progenitors, 2) regulation of stem cell niche during hair follicle cycle, 3) regulation of hair follicle stem cell niche upon injury.
Lab Staff
- Eve Kandyba- Postdoctoral Fellow
- Hanwei Zhang - Postdoctoral Research Associate
- Yvonne Leung- PhD Student