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Biology subjects

Munz, C. M.

Publications and source records attributed to Munz, C. M..

4 recordsLinked to original sources

Mast cells are not essential for pubertal mammary gland branching.

Mast cells are long-lived, tissue-resident immune cells of the myeloid lineage with cardinal functions in allergy and atopic disease. They are now increasingly recognized also for protective roles e.g. against infections and venoms. Other functions originally assigned to mast cells in development and physiology, however, have been refuted, and for yet others, their true contribution remains uncertain. Mast cells have been implicated in promoting ductal branching in the pubertal mammary gland, the organ that produces and secretes milk in mammals, but these findings are based on mouse models that are not mast cell-specific. In this study, we therefore re-addressed the impact of mast cells on mammary gland branching using several complementary genetic models, including a new transgenic line. We report that neither constitutive deficiency of mast cells, nor their conditional ablation induced at puberty affected mammary gland branching. Our results thus dispute that mast cells promote this process in mice, at least in a unique and non-redundant manner. This study adds to a growing body of work clarifying the biological roles of mast cells, and further expands the toolbox available to the field of mast cell research.

developmental biology↗

Emergency hematopoiesis proceeds without contribution of hematopoietic stem cells

Hematopoietic stem cells (HSCs) are the ultimate source of blood and immune cells. Under homeostatic conditions, these cells are considered a quiescent reserve population. However, it is not clear to what extent HSCs participate in emergency responses. Herein, we use fate mapping and proliferation tracking mouse models, which cumulatively record HSC activity in situ. We observed no direct contribution of HSCs to mature blood cell regeneration in response to common hematopoietic emergencies, including inflammation or blood loss. Innate immune training, in which HSCs were proposed to store and integrate information on previous infections, did not alter HSC activity upon secondary exposure. Only severe myeloablation resulted in a robust increase of HSC contribution. Our data demonstrates that HSCs do not directly participate in the regeneration of mature blood cells and therefore do not represent a reserve population to compensate for physiological hematopoietic perturbations.

cell biology↗

Hematopoietic lineages diverge within the stem cell compartment

Hematopoietic stem cells (HSCs) produce a highly diverse array of cell lineages. To assay hematopoietic differentiation with minimal experimental perturbation, non-invasive methods for heritable labeling1-3 or barcoding4-7 of HSCs in vivo have recently been developed and used to study lineage fate of HSCs in physiological conditions. However, the differentiation pathways leading from HSCs to mature cells remain controversial8, with suggested models ranging from gradual lineage restriction in a branching cascade of progenitors to HSCs already making ultimate lineage decisions. Here we show, by iterating HSC fate-mapping, mitotic history tracking, single-cell RNA-sequencing and computational inference, that the major differentiation routes to megakaryocytes, erythro-myeloid cells and lymphocytes split within HSCs. We identify the hitherto elusive self-renewing source of physiological hematopoiesis as an HSC subpopulation co-expressing high levels of Sca-1 and CD201. Downstream, HSCs reduce Sca-1 expression and enter into either thrombopoiesis or erythro-myelopoiesis, or retain high Sca-1 levels and the ability to generate lymphocytes. Moreover, we show that a distinct population of CD48-/lo megakaryocyte progenitors links HSCs to megakaryocytes. This direct thrombopoiesis pathway is independent of the classical pathway of megakaryocyte differentiation via multipotent progenitors and becomes the dominant platelet production line upon enhanced thrombopoietin signaling. Our results define a hierarchy of self-renewal and lineage decisions within HSCs in native hematopoiesis. Methodologically, we provide a blueprint for mapping physiological differentiation pathways of stem cells and probing their regulation.

systems biology↗

Proliferative behavior of hematopoietic stem cells revisited: No evidence for mitotic memory

The proliferative activity of adult hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that the most primitive HSCs divide only four times, to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in primitive HSCs with high repopulation potential. We argue that this background had been misinterpreted as retention of induced label and permanent quiescence. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support HSC mitotic memory and entry into permanent quiescence after few divisions, but show that primitive HSCs of adult mice continue to cycle rarely.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/745729v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (30K):\norg.highwire.dtl.DTLVardef@1b97626org.highwire.dtl.DTLVardef@fbc702org.highwire.dtl.DTLVardef@1c66b60org.highwire.dtl.DTLVardef@1b38f69_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗