Progenitor cell | EPFL Graph Search

A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only differentiate into their "target" cell type. The most important difference between stem cells and progenitor cells is that stem cells can replicate indefinitely, whereas progenitor cells can divide only a limited number of times. Controversy about the exact definition remains and the concept is still evolving. The terms "progenitor cell" and "stem cell" are sometimes equated. Properties Most progenitors are identified as oligopotent. In this point of view, they can compare to adult stem cells, but progenitors are said to be in a further stage of cell differentiation. They are "midway" between stem cells and fully differentiated cells. The kind of potency they have depends on the type of their "parent" stem cell and also on their niche. So

Asymmetric Cell Division in the Skin

Wan-Hung Fan

An asymmetric cell division (ACD) is defined as a division that gives rise to two daughter cells with different fates. It is the most common type of division during development. Analogous to Drosophila neuroblasts, proteins involved in ACD such as Insc and LGN are found to be asymmetrically localized during perpendicular cell divisions in mammalian skin, suggesting that the cutaneous tissue homeostasis may be controlled by using similar mechanisms. Most cell divisions in the basal layer of the skin are perpendicular to the basal membrane (BM), but when a skin tumor is formed, most cell divisions would become parallel to the BM. Previous studies in our lab have shown that regressing skin tumor caused by β-catenin depletion have increased perpendicular cell divisions accompanied by reduced stem cell numbers and enhanced mTrim2 expression. Furthermore, induced expression of mTRIM2 in skin tumors led to tumor regression. Taken together, this suggests that progenitor cells in the basal layer of the epidermis may use vertical ACDs to maintain progenitor cell number while using horizontal SCDs to expand progenitor cell number and mTrim2 may function as a cell fate determinant in skin. To validate the hypothesis that vertical divisions of basal keratinocytes to the BM are ACDs, I utilized light sheet based fluorescence microscopy (LSFM) to perform the time lapse recording of murine embryonic skin development between E14.5 and E17.5 and to monitor individual dividing cells and to track their fates after division. For visualizing the dividing cells, protein localization and differentiating cells, I have generated several transgenic mouse lines and combined them together. My study showed that ACD of basal keratinocytes can be either vertical or horizontal to the BM and divisions in the suprabasal layer can be both ACDs and SCDs. To study the potential function of mTRIMs in skin, I generated the knock-out (KO) mice. Neither mTrim2 KO, mTrim3 KO or mTrim32 KO mice showed any phenotype in skin, therefore I combined these mice to generate mTrim2/3 double KO and mTrim2/3/32 triple KO mice. Still, no skin phenotype was observed in these mice, indicating that mTrim2/3/32 might not function as a cell fate determinant in skin.

EPFL2012

Bioengineering human bone marrow models to elucidate the triggers of the stem cell niche

Queralt Vallmajó Martín

The bone marrow (BM) microenvironment, or niche, significantly affects behaviors of its resident stem cell populations. Disruptions in the BM niche contribute to a number of severe clinical pathologies. Discovery of novel therapeutic strategies for BM-related diseases necessitates development of superior preclinical models to study parameters affecting BM homeostasis. To address this, a poly(ethylene glycol) hydrogel featuring a particular crosslinking chemistry based on the enzyme transglutaminase factor XIII, dubbed TG-PEG, was utilized to engineer humanized bone marrow models. Its modular nature was exploited throughout this work to systematically evaluate contributions of biophysical, cellular, and biochemical BM niche components to stem cell biology. Stiffness of TG-PEG hydrogels was optimized for each cell type and individual application explored. For bone formation by bone marrow stromal cells (BMSCs), an intermediate stiffness was optimal and significantly improved total bone volume over softer TG-PEG gels or natural materials. Results indicated that stability of the scaffold was more important than their chemical and biological properties. Alternatively, for hematopoietic stem and progenitor cells (HSPCs), softer gels were optimal for preserving multipotency while promoting cell proliferation. A number of BM-specific stem and progenitor cell types with richly diverse functions were explored. Skeletal stem cells (SSCs) encapsulated in TG-PEG hydrogels demonstrated their ability to form de novo bone in healing critically sized calvaria defects in mice. Next, subcutaneous implantation of BMSC-laden gels revealed their significant contribution to formation of ossicles. For some BMSC donors, ossicles could be formed in absence of bone morphogenetic protein (BMP)-2 offering a novel tool to evaluate their intrinsic capacity. Later, titration of BMSC seeding densities and BMP-2 doses yielded optimal conditions for robust BM formation, regardless of donor, enabling reproducibility for follow-on studies involving BM models. In humanized mice, homing of HSPCs to BMSC-laden TG-PEG gels was observed. Finally, humanized xenograft models were employed to determine vulnerability of the BM niche to subversion by cancer cells simulating osteotropism for both leukemia and breast cancer metastasis. Molecular factors known to trigger particular cell reactions within the niche were also investigated. Including RGD cell-adhesion ligands, as well as matrix metalloproteinase (MMP)-susceptible crosslinks to render the gels degradable, were critical for facilitating migration of recruited BM cells from murine hosts in xenograft studies. Hyaluronic acid (HA), when added to the hydrogel backbone, conferred superior engraftment to transplanted BMSCs and afforded reduced immunogenicity. Incorporation of the Notch-signaling ligands Jagged1 or DLL-4 into soft TG-PEG gels during in vitro HSPC expansion substantially stimulated proliferation, but recovered cells could no longer ensure long-term reconstitution. Aging, trauma, or cancer can cause disruptions of the tightly controlled balance between cells and their microenvironment in the BM niche. This body of work presents a number of bioengineered tools optimized for studying how niche components are affected by or contribute to such pathologies. Further work with these or similar models will no doubt highlight key clinically relevant targets and inform novel therapeutic approaches.

EPFL2019