A Limited Role for AMD3100 Induced Stem Cell Mobilization for Modulation of Thoracic Trauma Outcome.

ABSTRACT: Thoracic trauma is a major cause of mortality due to the associated inflammatory acute respiratory distress syndrome and morbidity due to impaired tissue regeneration. Trauma-induced lung inflammation is characterized by the early recruitment of cells with pro- or anti-inflammatory activity to the lung. Therapeutic interventions reducing the level of tissue inflammation may result in decreased tissue damage and improved healing and recovery. Stem cells might be able to improve trauma outcome via immunomodulation or by enhancing tissue regeneration.Here, we describe the migratory dynamics of murine mesenchymal, hematopoietic and endothelial stem and progenitor cells (SPCs) as well as mature inflammatory cells (monocytes, neutrophils, lymphocytes) to peripheral blood (PB) and lung tissue between 0.2 and 48 h post-blunt chest trauma (TXT). We demonstrate that the kinetics of immune cell and SPC distribution upon trauma are both cell-type and tissue-dependent. We identified a transient, early increase in the number of inflammatory cells in PB and lung at 2 h post-TXT and a second wave of infiltrating SPCs in lungs by 48 h after TXT induction, suggesting a role for SPCs in tissue remodeling after the initial inflammatory phase. Cxcl12/Cxcr4 blockade by AMD3100 within the first 6 h after TXT, while inducing a strong and coordinated mobilization of SPCs and leukocytes to PB and lung tissue, did not significantly affect TXT associated inflammation or tissue damage as determined by inflammatory cytokine levels, plasma markers for organ function, lung cell proliferation and survival, and myofibroblast/fibroblast ratio in the lung. Further understanding the dynamics of the distribution of endogenous SPCs and inflammatory cells will therefore be indispensable for stem cell-based or immunomodulation therapies in trauma.

Reduced adhesion of aged intestinal stem cells contributes to an accelerated clonal drift.

Upon aging, the function of the intestinal epithelium declines with a concomitant increase in aging-related diseases. ISCs play an important role in this process. It is known that ISC clonal dynamics follow a neutral drift model. However, it is not clear whether the drift model is still valid in aged ISCs. Tracking of clonal dynamics by clonal tracing revealed that aged crypts drift into monoclonality substantially faster than young ones. However, ISC tracing experiments, in vivo and ex vivo, implied a similar clonal expansion ability of both young and aged ISCs. Single-cell RNA sequencing for 1,920 high Lgr5 ISCs from young and aged mice revealed increased heterogeneity among subgroups of aged ISCs. Genes associated with cell adhesion were down-regulated in aged ISCs. ISCs of aged mice indeed show weaker adhesion to the matrix. Simulations applying a single cell-based model of the small intestinal crypt demonstrated an accelerated clonal drift at reduced adhesion strength, implying a central role for reduced adhesion for affecting clonal dynamics upon aging.

Distinct Dynamics of Stem and Progenitor Cells in Blood of Polytraumatized Patients.

Endogenously mobilized stem and progenitor cells (SPCs) or exogenously provided SPCs are thought to be beneficial for trauma therapy. However, still little is known about the synchronized dynamics of the number of SPCs in blood after severe injury and parameters like cytokine profiles that correlate with these numbers. We determined the number of hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and mesenchymal stem/stromal cells in peripheral blood (PB) 0 to 3, 8, 24, 48, and 120 h after polytrauma in individual patients (injury severity score ≥ 21). We found that the number of blood SPCs follows on average a synchronous, inverse bell-shaped distribution, with an increase at 0 to 3 h, followed by a strong decrease, with a nadir in SPC numbers in blood at 24 or 48 h. The change in numbers of SPCs in PB between 48 h and 120 h revealed two distinct patterns: Pattern 1 is characterized by an increase in the number of SPCs to a level higher than normal, pattern 2 is characterized by an almost absent increase in the number of SPCs compared to the nadir. Changes in the concentrations of the cytokines CK, MDC, IL-8, G-CSF Gro-α, VEGF, and MCP-1 correlated with changes in the number of SPCs in PB or were closely associated with Pattern 1 or Pattern 2. Our data provide novel rationale for investigations on the role of stem cell mobilization in polytraumatized patients and its likely positive impact on trauma outcome.