| 1. |
- Böiers, Charlotta, et al.
(author)
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Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells.
- 2013
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In: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 13:5, s. 535-548
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Journal article (peer-reviewed)abstract
- In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis.
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| 2. |
- Deng, Qiaolin
(author)
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The role of Lmx1a and Lmx1b in regulating mesencephalon development and dopamine neuron specification
- 2010
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Doctoral thesis (other academic/artistic)abstract
- One of the most challenging questions in developmental biology is how neurons are specified, acquire their distinct characteristics and find their correct innervations to form functional circuits. The development of different subsets of neurons involves the expression of a program intrinsic to each cell type and the response to extrinsic environmental influences represented by soluble factors. Breakthroughs in the understanding of the genetic programs that controls the specification of ventral cell fates in the spinal cord and hindbrain, have provided useful tools for the study of similar genetic networks in the more complex rostral regions of the central nervous system, such as the mesencephalon (also called midbrain). Midbrain dopamine (mDA) neurons are born in the ventral midline of the midbrain and regulate important functions in the brain, including motor control, cognition, emotions and learning. The degeneration of mDA neurons is the major hallmark of Parkinson s disease (PD). The lack of knowledge regarding the factors involving in the early specification of mDA neurons has been one of the obstacles in applying embryonic stem cell (ESC)-based replacement therapy for PD. In paper I, we showed that Lmx1a and Msx1/2 are two key components in the development of mDA neurons. Lmx1a is necessary and sufficient for the acquisition of the proper mDA fate by activating the expression of downstream mDA neuron markers, while Msx1/2 synergizes with Lmx1a by suppressing alternative cell fates and promoting the progression of neurogenesis. Furthermore, we applied this knowledge to ESCs and showed that forced expression of Lmx1a could efficiently induce bona fide mDA neurons. In paper II, we continued to evaluate the role of Lmx1a in the mouse and compared the function of Lmx1a with its close homolog Lmx1b during mDA development. Surprisingly, loss of Lmx1a resulted in a moderate reduction of mDA neurons, which was partly due to the delayed conversion of floor plate into a neurogenic region at an early stage. Lmx1b could compensate to large extent for the loss of Lmx1a in mDA neuron generation as the compound genotype of the Lmx1 genes displayed a dose-dependent effect. Importantly, we showed that Lmx1a and Lmx1b have distinct roles in specifying two subgroups, i.e. medial and lateral mDA neurons. In addition, we revealed the function of Lmx1b in patterning other ventral cell types, i.e. oculomotor (OM) neurons and red nucleus (RN) cells. Loss of Lmx1b caused a dramatic reduction of OM neurons. By contrast, RN cells were born prematurely and were overproduced. Our current findings establish that Lmx1b influences the differentiation of multiple neuronal subtypes in the ventral midbrain, while the activity of Lmx1a in the ventral midbrain appears devoted to the differentiation of mDA neurons.
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| 3. |
- Woll, Petter S, et al.
(author)
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Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.
- 2014
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In: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 25:6, s. 794-808
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Journal article (peer-reviewed)abstract
- Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
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