Honors & Awards
Postdoctoral Young Investigator Award., Stanford Institute for Stem Cell Biology and Regenerative Medicine (2017)
Recipient of the Inaugural: "Scholarship in Foetal Medicine"., University of Descartes, Paris V, France (2012)
Recipient of the Inaugural: "UCD-Harvard Summer Studentship", Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (2012)
Health Research Board (HRB) "Oral Competition Finalist", Dublin Castle, HRB (2011)
Student Summer Research Award SSRA Medal Winner, University College Dublin (2010)
University College Dublin Entrance Award, University College Dublin (2007)
Boards, Advisory Committees, Professional Organizations
Member of The Royal College of Surgeons Ireland, Royal College of Surgeons Ireland (RCSI) (2015 - Present)
B of Medicine and B of Surgery, University College Dublin (2013)
Michael Longaker, Postdoctoral Faculty Sponsor
Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration.
During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which isa process that is used in humans to correct an undersized lower jawthat involves surgically separating the jaw bone, whichelicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.
View details for PubMedID 30356216
- Method of Isolating and Transplanting the Hematopoietic Stem Cell with Its Microenvironment Which Improves Functional Hematopoietic Engraftment ELSEVIER SCIENCE INC. 2018: E224
- Translational Approach Using Trimodal Manipulation of Resident Skeletal Stem Cells for Articular Cartilage Repair ELSEVIER SCIENCE INC. 2018: S213–S214
- Reduced Scar Thickness Achieved by Topical Doxycycline Is Mediated by Specific Skin Fibroblast Populations and Not Immune Cell Infiltrate ELSEVIER SCIENCE INC. 2018: S210–S211
Identification of the Human Skeletal Stem Cell.
2018; 175 (1): 43
Stem cell regulation and hierarchical organization ofhuman skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis. VIDEO ABSTRACT.
View details for PubMedID 30241615
Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.
2018; 9 (1): 2971
Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through thepackaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.
View details for PubMedID 30061668
Isolation and functional assessment of mouse skeletal stem cell lineage
2018; 13 (6): 1294–1309
There are limited methods available to study skeletal stem, progenitor, and progeny cell activity in normal and diseased contexts. Most protocols for skeletal stem cell isolation are based on the extent to which cells adhere to plastic or whether they express a limited repertoire of surface markers. Here, we describe a flow cytometry-based approach that does not require in vitro selection and that uses eight surface markers to distinguish and isolate mouse skeletal stem cells (mSSCs); bone, cartilage, and stromal progenitors (mBCSPs); and five downstream differentiated subtypes, including chondroprogenitors, two types of osteoprogenitors, and two types of hematopoiesis-supportive stroma. We provide instructions for the optimal mechanical and chemical digestion of bone and bone marrow, as well as the subsequent flow-cytometry-activated cell sorting (FACS) gating schemes required to maximally yield viable skeletal-lineage cells. We also describe a methodology for renal subcapsular transplantation and in vitro colony-formation assays on the isolated mSSCs. The isolation of mSSCs can be completed in 9 h, with at least 1 h more required for transplantation. Experience with flow cytometry and mouse surgical procedures is recommended before attempting the protocol. Our system has wide applications and has already been used to study skeletal response to fracture, diabetes, and osteoarthritis, as well as hematopoietic stem cell-niche interactions in the bone marrow.
View details for PubMedID 29748647
Scarless wound healing: Transitioning from fetal research to regenerative healing.
Wiley interdisciplinary reviews. Developmental biology
2018; 7 (2)
Since the discovery of scarless fetal skin wound healing, research in the field has expanded significantly with the hopes of advancing the finding to adult human patients. There are several differences between fetal and adult skin that have been exploited to facilitate scarless healing in adults including growth factors, cytokines, and extracellular matrix substitutes. However, no one therapy, pathway, or cell subtype is sufficient to support scarless wound healing in adult skin. More recently, products that contain or mimic fetal and adult uninjured dermis were introduced to the wound healing market with promising clinical outcomes. Through our review of the major experimental targets of fetal wound healing, we hope to encourage research in areas that may have a significant clinical impact. Additionally, we will investigate therapies currently in clinical use and evaluate whether they represent a legitimate advance in regenerative medicine or a vulnerary agent. WIREs Dev Biol 2018, 7:e309. doi: 10.1002/wdev.309 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Plant Development > Cell Growth and Differentiation Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells.
View details for PubMedID 29316315
Calvarial Defects: Cell-Based Reconstructive Strategies in the Murine Model
TISSUE ENGINEERING PART C-METHODS
2017; 23 (12): 971–81
Calvarial defects pose a continued clinical dilemma for reconstruction. Advancements within the fields of stem cell biology and tissue engineering have enabled researchers to develop reconstructive strategies using animal models. We review the utility of various animal models and focus on the mouse, which has aided investigators in understanding cranial development and calvarial bone healing. The murine model has also been used to study regenerative approaches to critical-sized calvarial defects, and we discuss the application of stem cells such as bone marrow-derived mesenchymal stromal cells, adipose-derived stromal cells, muscle-derived stem cells, and pluripotent stem cells to address deficient bone in this animal. Finally, we highlight strategies to manipulate stem cells using various growth factors and inhibitors and ultimately how these factors may prove crucial in future advancements within calvarial reconstruction using native skeletal stem cells.
View details for PubMedID 28825366
View details for PubMedCentralID PMC5734144
- Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle- Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects PLASTIC AND RECONSTRUCTIVE SURGERY 2017; 139 (4): 906-907
The Role of Skeletal Stem Cells in the Reconstruction of Bone Defects.
The Journal of craniofacial surgery
2017; 28 (5): 1136–41
Craniofacial surgery, since its inauguration, has been the culmination of collaborative efforts to solve complex congenital, dysplastic, oncological, and traumatic cranial bone defects. Now, 50 years on from the first craniofacial meeting, the collaborative efforts between surgeons, scientists, and bioengineers are further advancing craniofacial surgery with new discoveries in tissue regeneration. Recent advances in regenerative medicine and stem cell biology have transformed the authors' understanding of bone healing, the role of stem cells governing bone healing, and the effects of the niche environment and extracellular matrix on stem cell fate. This review aims at summarizing the advances within each of these fields.
View details for PubMedID 28665863