Centre for Stem Cell Research
phone 713.500.3429; fax 713.500.2424
Jeannie A. Javni, Ph.D., Research Manager 713.500.3428
Paul J Simmons, Ph.D., Professor & Director
Nathalie Brouard, Ph.D., Instructor
Brian R. Davis, Ph.D., Associate Professor
Mikhail G. Kolonin, Ph.D., Assistant Professor
Nami McCarty, Ph.D., Assistant Professor
Naoki Nakayama, Ph.D., Associate Professor
A major focus of contemporary medicine is the development of effective therapies for the restoration of human tissues and organs lost to diseases and trauma. Regenerative Medicine is a rapidly emerging field that stands at the intersection of a variety of rapidly developing scientific disciplines: stem cell biology, tissue engineering, biomaterials, molecular biology, immunology and transplantation biology and clinical research. Implicit in the successful design, implementation and application of regenerative medicine/tissue engineering approaches to the repair of a damaged tissue or organ is the reliance on the unique biological properties of stem cells.
The mission statement of the Centre for Stem Cell research at the IMM is: To study the fundamental properties of stem cells and to translate their unique biological properties into novel cellular therapies for graft engineering and tissue regeneration for currently intractable disorders. While it is therefore implicit that any such program would span basic-translational-clinical research, it is essential that such an endeavour is ultimately underpinned by excellence in fundamental stem cell research. The Director of the Center, Dr Paul Simmons is currently in the process of recruiting a multidisciplinary faculty with the appropriate breadth of expertise, innovation and scientific rigour in the discipline of stem cell biology with the dual intention to promote the excellence and innovation of research within the Center and secondly to ensure the quality and appropriateness of stem cell based translational research initiatives emanating from the Center. In addition, the Center is also envisioned as an educational resource, which in the medium to long-term will be the basis for the development of an academic program in stem cell biology on campus. Moreover, by interfacing effectively with other programs and institutions within the UT-HSC, the Center will also act as a focus to stimulate the development and implementation of novel cellular therapies for a range of diseases and disorders.
Some of the current areas of research in the Center are highlighted below:
Life’s a Niche and then you Die Understanding the interplay between cell intrinsic properties and extrinsic regulators is at the heart of stem cell physiology. The notion of the stem cell niche as a cellular environment with unique stem cell regulatory properties was first proposed based upon studies of the hematopoietic system but is now widely embraced as a cardinal feature of stem cell physiology in most if not all adult tissues and organs. Efforts underway in the laboratories of Drs Nathalie Brouard and Nami McCarty seek to define the cellular and molecular constituents of the hematopoietic stem cell (HSC) niche based upon analysis of niche-forming cells prospectively isolated from fetal liver and from the bone and endothelial vasculature of the adult bone marrow. the This is emerging as a powerful approach to the identification of novel and previously unrecognized hematopoietic regulators. The broad aim will be to exploit knowledge gained from this molecular dissection to develop an in vitro facsimile of the HSC niche in the form of a bioarray of recombinant molecules that reflects the complex molecular composition of the niche. By providing a more effective means to recapitulate niche function ex vivo than with soluble growth factors alone, it is anticipated this strategy will lead to the development of ‘smart’, niche-based bioreactors for improved large-scale cultivation of HSC. Studies in collaboration with the laboratory of Dr Elizabeth J Shpall at the UT-MD Anderson Cancer Center are already underway which seek to apply this approach to improving the growth of primitive hematopoietic progenitors from human umbilical cord blood with the aim to improve the rapidity of engraftment. According to this approach, the stem cell niche is viewed as a novel therapeutic target, a concept which in principle could be applied to the development of improved culture conditions for the propagation of stem cells from a wide range of adult tissues. It is further anticipated that this approach will ultimately lead to novel approaches for stimulating in vivo regeneration through the stimulation of repair by endogenous stem cells.
Cellular therapies for the repair of the skeleton and the spinal cord The stromal tissue of the bone marrow represents the microenvironment of the bone marrow which provides both physical and functional support for hematopoiesis. Dr Paul Simmons’ lab has had a longstanding interest in the properties of precursor cells for the stromal system of the bone marrow culminating in the first prospective isolation of putative marrow stromal stem cells (MSC) from adult human and more recently, mouse, bone marrow. One focus in his lab is to exploit the well-documented capacity of these cells to differentiate into the osteogenic lineage as a cellular therapy for the treatment of large segmental (non-union) defects in bone resulting from traumatic injury or as a consequence of surgical resection in the treatment of cancer. Another clinical application being pursued is the use of MSC in the treatment of spinal cord damage. Based on preclinical studies performed in Australia as part of his role as Scientific Advisor to the Spinal Cord Society of Australia (SCSA), it is hoped that this initiative will be greatly stimulated by Dr Simmons’ recent membership of Mission Connect, a unique collaborative research effort led by TIRR Foundation.
Stem cells in the genesis of cancer Accumulating evidence suggests that similar signalling pathways may contribute to the regulation of self-renewal in stem cells and tumour cells. In accord with this, a concept proposed many years ago but only now receiving critical evaluation, suggests that tumours may arise as a consequence of the transformation of normal stem cells or their immediate progeny. The identification and isolation of these so-called cancer or tumour-initiating stem cells is a major focus for many research groups given the probability that these cells represent more relevant targets for the development of improved therapeutic strategies for the treatment of cancer. Dr. McCarty's lab is currently investigating whether lymphomas exhibit a hierarchical organization and whether a minor population of cells within the tumour distinguished by a unique cell surface phenotype (putative lymphoma-initiating cells) demonstrate the capacity to initiate and form new tumors.
A cancer cell is not an island: Role of the tissue microenvironment A rapidly emerging area of considerable interest is the role played by the tumour microenvironment in the pathogenesis of cancer. Burgeoning evidence demonstrates that in common with stem cells in normal healthy tissues whose properties are regulated by their interactions with their stem cell niche, the behaviour of tumour cells is also strongly influenced by their interactions with the surrounding tissue microenvironment. Indeed, accumulating data support the concept of cancer as a disease that must simultaneously subvert the microenvironmental controls as well as the genetic program. White adipose tissue is an abundant source of MSC that may serve as progenitor cells for tumor vasculature and thus promote cancer progression. The laboratory of Dr Mikhail Kolonin is focusing on exploring the role of adult stem cells in tumor vasculogenesis and on defining the mechanisms responsible for activating the mobilization of adipose stem cells from their niche in the fat tissue and for their homing and engraftment at sites of tumour formation.
Editing the genome of stem cells The research in Dr. Davis’ laboratory focuses ion the use of homologous recombination and/or DNA repair processes to restore an endogenous mutant gene sequence to the corrected normal sequence. This approach of gene editing when performed in stem cells from an individual with an inherited genetic disease has the potential to generate a source of autologous normal stem cells that may provide an effective therapy to treat the disease. Dr Davis is also utilizing this approach as an experimental tool to introduce specific changes (e.g. SNPs) into genes in normal stem cells as a means to investigate the functional consequences of such changes. A parallel track of investigation is focused on spontaneous somatic reversion of inherited mutations or “natural gene therapy” in patients with inherited genetic disease. This project which developed out of Dr Davis’ identification of numerous genetic revertants in a patient with Wiskott-Aldrich Syndrome, provides an unprecedented snapshot of natural selection at work within a patient with an inherited genetic disease – acting upon a repertoire of mutant genotypes to select those encoding protein(s) with greatest functionality.