Progenitor Cell Populations Research Articles

Deciphering Metabolic Adaptability of Leukemic Stem Cells.

Therapeutic targeting of leukemic stem cells is widely studied to control leukemia. An emerging approach gaining popularity is altering metabolism as a potential therapeutic opportunity. Studies have been carried out on hematopoietic and leukemic stem cells to identify vulnerable pathways without impacting the non-transformed, healthy counterparts. While many metabolic studies have been conducted using stem cells, most have been carried out in vitro or on a larger population of progenitor cells due to challenges imposed by the low frequency of stem cells found in vivo. This creates artifacts in the studies carried out, making it difficult to interpret and correlate the findings to stem cells directly. This review discusses the metabolic difference seen between hematopoietic stem cells and leukemic stem cells across different leukemic models. Moreover, we also shed light on the advancements of metabolic techniques and current limitations and areas for additional research of the field to study stem cell metabolism.

Newly identified breast luminal progenitor and gestational stem cell populations likely give rise to HER2-overexpressing and basal-like breast cancers

Breast Cancer (BrC) is a common malignancy with genetically diverse subtypes. There is evidence that specific BrC subtypes originate from particular normal mammary cell populations. However, the cell populations that give rise to most BrC subtypes are unidentified. Several human breast scRNAseq datasets are available. In this research, we utilized a robust human scRNAseq dataset to identify population-specific marker genes and then identified the expression of these marker genes in specific BrC subtypes. In humans, several BrC subtypes, HER2-enriched, basal-like, and triple-negative (TN), are more common in women who have had children. This observation suggests that cell populations that originate during pregnancy give rise to these BrCs. The current human datasets have few normal parous samples, so we supplemented this research with mouse datasets, which contain mammary cells from various developmental stages. This research identified two novel normal breast cell populations that may be the origin of the basal-like and HER2-overexpressing subtypes, respectively. A stem cell-like population, SC, that expresses gestation-specific genes has similar gene expression patterns to basal-like BrCs. A novel luminal progenitor cell population and HER2-overexpressing BrCs are marked by S100A7, S100A8, and S100A9 expression. We bolstered our findings by examining SC gene expression in TN BrC scRNAseq datasets and S100A7-A9 gene expression in BrC cell lines. We discovered that several potential cancer stem cell populations highly express most of the SC genes in TN BrCs and confirmed S100A8 and A9 overexpression in a HER2-overexpressing BrC cell line. In summary, normal SC and the novel luminal progenitor cell population likely give rise to basal-like and HER2-overexpressing BrCs, respectively. Characterizing these normal cell populations may facilitate a better understanding of specific BrCs subtypes.

N‑acetyl cysteine prevents ambient fine particulate matter‑potentiated atherosclerosis via inhibition of reactive oxygen species‑induced oxidized low density lipoprotein elevation and decreased circulating endothelial progenitor cell.

Ambient fine particulate matter (PM) serves an important role in the development of cardiovascular disease, including atherosclerosis. Antioxidant N-acetyl cysteine (NAC) has protective effects in the cardiovascular system. However, it is unknown if NAC prevents PM-potentiated atherosclerosis in hyperlipidemia. Low-density lipoprotein (LDL) receptor knockout mice were pretreated with 1 mg/ml NAC in drinking water for 1 week and continued to receive NAC, high-fat diet and intranasal instillation of PM for 1 week or 6 months. Blood plasma was collected for lipid profile, oxidized (ox-)LDL, blood reactive oxygen species (ROS) and inflammatory cytokine (TNF-α, IL-1β and IL-6) measurement. Blood cells were harvested for endothelial progenitor cell (EPC) population and intracellular ROS analysis. Murine aorta was isolated for atherosclerotic plaque ratio calculation. NAC treatment maintained circulating EPC level and significantly decreased blood ox-LDL and ROS, inflammatory cytokines, mononuclear and EPC intracellular ROS levels as well as aortic plaque ratio. NAC prevented PM-potentiated atherosclerosis by inhibiting plasma ROS-induced ox-LDL elevation, mononuclear cell and EPC intracellular ROS-induced circulating EPC reduction and inflammatory cytokine production.

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia.

The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13-driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2-driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.

Chidamide and apatinib are therapeutically synergistic in acute myeloid leukemia stem and progenitor cells

BackgroundLeukemia stem cells (LSCs) are responsible for the initiation and perpetuation of acute myeloid leukemia (AML), and also represent leukemia relapse reservoirs with limited therapeutic approaches. Thus, additional treatment strategies are medical unmet needs to eliminate LSCs.MethodsCell counting kit-8 and Annexin-V-FITC/PI assays were used to examine the interaction of chidamide and apatinib on LSC-like cell lines (CD34+CD38− KG1α and Kasumi-1 cells) and primary CD34+ AML cells. AML patient-derived xenografts were established to investigate the in vivo efficacy of the combined regimen. RNA sequencing, Glutamine uptake assay, oxygen consumption assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of chidamide with or without apatinib against LSC-like cell lines and/or primary CD34+ AML cells.ResultsIn this study, chidamide and apatinib were synergisitc to diminish cell viability and induce apoptosis in CD34+CD38− KG1α and Kasumi-1 cells and in CD34+ primary AML cells. Importantly, chidamide combined with apatinib had more powerful in reducing leukemia burden and improving prognosis than single drug alone in an AML PDX model without significant adverse effects. Chidamide cytotoxicity was associated with decreasing glutamine uptake. The therapeutic synergy of chidamide and apatinib correlated with reprogramming of energy metabolic pathways. In addition, inactivating the VEGFR function and reducing the anti-apoptotic ability of the Bcl2 family contributed to the synergism of chidamide and apatinib in CD34+CD38− KG1α cells and CD34+ primary AML cells.ConclusionChidamide in combination with apatinib might be a promising therapeutic strategy to get rid of the population of AML stem and progenitor cells, and thus provide a potentially curative option in the treatment of patients with AML, although further clinical evaluations are required to substantiate the conclusion.

Human Peripheral Blood Mononucleocyte Derived Myeloid Committed Progenitor Cells Mitigate H-ARS by Exosomal Paracrine Signal.

Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient’s hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome.

DLK1 expressing cells mark a population of progenitor cells in the adrenal cortex and contribute to the zonation of the adrenal gland

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Conservation of Kidney Development in the Red‐eared Slider, Trachemys scripta

Mammals, birds, and reptiles all possess a metanephric kidney in adult animals. The process of kidney development, or nephrogenesis, ceases in mammals prior to or immediately after birth. Termination of mammalian nephrogenesis is due to kidney progenitor cell populations halting self‐renewal and undergoing terminal differentiation. Our previous studies have shown in several reptile species the presence of post‐embryonic nephrogenesis accompanying embryonic‐like adult progenitor cells. It is unknown how or why kidney progenitor cell populations are lost during mammalian development but persist in reptiles. To better understand the persistence of kidney progenitor cells in reptiles, we have set out to characterize kidney development to determine if adult progenitor cell populations are a continuation of embryonic processes. We have chosen to use the red‐eared slider turtle, Trachemys scripta, as a model for reptile metanephric kidney development as this species showed the highest number of nephrogenic zones in adults. While the embryonic development of external morphology (such as head, limbs, shell) in this species has been documented, organogenesis has not been studied as thoroughly. We have utilized gross observations of morphology, histology, whole‐mount immunohistochemistry and in situ hybridization to characterize and assess the conservation of kidney development in this species. The embryonic kidney progenitor cell marker, Six2, was detected as early as stage‐15 as a linear group of metanephric mesenchyme. Little to no cytokeratin positive epithelium was detected at this stage of kidney development. As kidney development proceeds, the progenitor mesenchyme cells and adjacent ureteric bud epithelium are found in highly organized rows. Several genes known to play roles within mammalian kidney development displayed conserved expression domains in the developing T. scripta kidney. The embryonically expressed Six2 transcription factor was also detected in progenitor cells of adult kidneys. Future investigation will continue to assess kidney ontogeny in reptiles.

Abstract 109: The Chromatin Remodeling Protein Brg1 Regulates Adventitial Progenitor Cell Myofibroblast Differentiation And Pathological Vascular Remodeling

Cardiovascular diseases lead to long-term stiffening of arteries and small vessels. The vascular wall contains several cellular populations that coordinate to maintain vessel homeostasis and induce vascular remodeling in disease states. We identified a population of smooth muscle-derived progenitor cells that reside in the adventitial layer (AdvSca1-SM cells) that drive vascular fibrosis after acute vascular injury. AdvSca1-SM cells can differentiate into myofibroblasts and secrete numerous pro-remodeling factors including extracellular matrix proteins and pro-inflammatory cytokines. While the response of AdvSca1-SM cells to vascular injury has been studied, the epigenetic changes that influence their differentiation towards myofibroblasts is poorly understood. We observed Brahma-related gene 1 (Brg1), a highly conserved chromatin remodeling ATPase, is upregulated in AdvSca1-SM cells in response to vascular injury and may be a key factor in regulating gene expression to influence AdvSca1-SM differentiation. We hypothesize that Brg1 induces expression of gene sets associated with remodeling and fibrosis and ultimately drives AdvSca1-SM cell differentiation towards pathologic myofibroblasts. Results: Carotid arteries from mice subject to carotid ligation exhibit decreased perivascular collagen deposition, smaller neointima, decreased adventitial expansion, decreased numbers of alpha-actin positive AdvSca1-SM cells, and fewer infiltrating macrophages when treated with the pharmacological Brg1 bromodomain inhibitor PFI-3 as compared to mice that received vehicle control. In a cell culture system, TGF-β induces AdvSca1-SM cells to express myofibroblast-specific genes, including alpha actin and periostin, and demonstrate enhanced contractile function in collagen contraction assays. PFI-3 blocks TGF-β induced myofibroblast gene expression and dampens contractile function. Gene Ontology analysis reveals the top 100 TGF-β inducible genes blunted by PFI-3 are related to fibrosis and extracellular matrix signaling. In conclusion, these results suggest Brg1 is a major regulator of vascular remodeling and fibrosis and may be a targetable protein to help people who suffer from disease-related vascular stiffening.

Abstract 208: The Chromatin Remodeling Protein Brg1 Regulates Adventitial Progenitor Cell Myofibroblast Differentiation And Pathological Vascular Remodeling

Cardiovascular diseases lead to long-term stiffening of arteries and small vessels. The vascular wall contains several cellular populations that coordinate to maintain vessel homeostasis and induce vascular remodeling in disease states. We identified a population of smooth muscle-derived progenitor cells that reside in the adventitial layer (AdvSca1-SM cells) that drive vascular fibrosis after acute vascular injury. AdvSca1-SM cells can differentiate into myofibroblasts and secrete numerous pro-remodeling factors including extracellular matrix proteins and pro-inflammatory cytokines. While the response of AdvSca1-SM cells to vascular injury has been studied, the epigenetic changes that influence their differentiation towards myofibroblasts is poorly understood. We observed Brahma-related gene 1 (Brg1), a highly conserved chromatin remodeling ATPase, is upregulated in AdvSca1-SM cells in response to vascular injury and may be a key factor in regulating gene expression to influence AdvSca1-SM differentiation. We hypothesize that Brg1 induces expression of gene sets associated with remodeling and fibrosis and ultimately drives AdvSca1-SM cell differentiation towards pathologic myofibroblasts. Results: Carotid arteries from mice subject to carotid ligation exhibit decreased perivascular collagen deposition, smaller neointima, decreased adventitial expansion, decreased numbers of alpha-actin positive AdvSca1-SM cells, and fewer infiltrating macrophages when treated with the pharmacological Brg1 bromodomain inhibitor PFI-3 as compared to mice that received vehicle control. In a cell culture system, TGF-β induces AdvSca1-SM cells to express myofibroblast-specific genes, including alpha actin and periostin, and demonstrate enhanced contractile function in collagen contraction assays. PFI-3 blocks TGF-β induced myofibroblast gene expression and dampens contractile function. Gene Ontology analysis reveals the top 100 TGF-β inducible genes blunted by PFI-3 are related to fibrosis and extracellular matrix signaling. In conclusion, these results suggest Brg1 is a major regulator of vascular remodeling and fibrosis and may be a targetable protein to help people who suffer from disease-related vascular stiffening.

Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity

Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the “anti-proteinase” molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.

The Vitamin A Paradox: Too Much or Too Little Impacts Development and Disease

Vitamin A is essential for proper human embryonic development particularly with respect to brain, craniofacial, limb, and organ, patterning and morphogenesis. Later, in adulthood, vitamin A plays important roles in fertility, immune function, maintenance of vision, and skeletal homeostasis. Surprisingly, deficiency or excess of vitamin A and its metabolic derivative, retinoic acid, can elicit similar effects. Therefore, strict feedback and other mechanisms must exist to regulate levels within a narrow physiological range. We discovered retinol dehydrogenase 10 (Rdh10) as a novel critical regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. Rdh10 oxidizes all trans retinol (vitamin A) to retinal, which is then oxidized by retinaldehyde dehydogenases to retinoic acid. Rdh10 loss‐of‐function mouse embryos exhibit craniofacial anomalies such as choanal atresia, facial clefts, and abnormal branchiomeric muscle development, cardiac malformations including choanal atresia, and gastrointestinal defects such as Hirschsprung disease. Underpinning each phenotype were defects in the development of neural crest cells, a migratory progenitor cell population essential for normal craniofacial and organ morphogenesis. We determined that Rdh10 and retinoic acid signaling are precisely required between embryonic day (E) 7.5‐9.5 in both an intrinsic/autocrine and extrinsic/paracrine manner for proper neural crest cell development. Thus, Rdh10 forms a key nodal point in the regulation of vitamin A metabolism and retinoic acid synthesis and is essential for regulating basic developmental and homeostasis signaling pathways. Furthermore, Rdh10 and vitamin A signaling are both genetic and non‐genetic risk factors in the etiology and pathogenesis of congenital birth defects.

Bone Marrow-Derived Cells Contribute to the Maintenance of Thymic Stroma including TECs.

In paradox to critical functions for T-cell selection and self-tolerance, the thymus undergoes profound age-associated atrophy and loss of T-cell function, further enhanced by cancer therapies. Identifying thymic epithelial progenitor populations capable of forming functional thymic tissue will be critical in understanding thymic epithelial cell (TEC) ontogeny and designing strategies to reverse involution. We identified a new population of progenitor cells, present in both the thymus and bone marrow (BM) of mice, that coexpress the hematopoietic marker CD45 and the definitive thymic epithelial marker EpCAM and maintain the capacity to form functional thymic tissue. Confocal analysis and qRT-PCR of sorted cells from both BM and thymus confirmed coexpression of CD45 and EpCAM. Grafting of C57BL/6 fetal thymi under the kidney capsule of H2BGFP transgenic mice revealed that peripheral CD45+ EpCAM+ GFP-expressing cells migrate into the developing thymus and contribute to both TECs and FSP1-expressing thymic stroma. Sorted BM-derived CD45+ EpCAM+ cells contribute to reaggregate thymic organ cultures (RTOCs) and differentiate into keratin and FoxN1-expressing TECs, demonstrating that BM cells can contribute to the maintenance of TEC microenvironments previously thought to be derived solely from endoderm. BM-derived CD45+ EpCAM+ cells represent a new source of progenitor cells that contribute to thymic homeostasis. Future studies will characterize the contribution of BM-derived CD45+ EpCAM+ TEC progenitors to distinct functional TEC microenvironments in both the steady-state thymus and under conditions of demand. Cell therapies utilizing this population may help counteract thymic involution in cancer patients.

Foregut organ progenitors and their niche display distinct viscoelastic properties in vivo during early morphogenesis stages

Material properties of living matter play an important role for biological function and development. Yet, quantification of material properties of internal organs in vivo, without causing physiological damage, remains challenging. Here, we present a non-invasive approach based on modified optical tweezers for quantifying sub-cellular material properties deep inside living zebrafish embryos. Material properties of cells within the foregut region are quantified as deep as 150 µm into the biological tissue through measurements of the positions of an inert tracer. This yields an exponent, α, which characterizes the scaling behavior of the positional power spectra and the complex shear moduli. The measurements demonstrate differential mechanical properties: at the time when the developing organs undergo substantial displacements during morphogenesis, gut progenitors are more elastic (α = 0.57 ± 0.07) than the neighboring yolk (α = 0.73 ± 0.08), liver (α = 0.66 ± 0.06) and two mesodermal (α = 0.68 ± 0.06, α = 0.64 ± 0.06) progenitor cell populations. The higher elasticity of gut progenitors correlates with an increased cellular concentration of microtubules. The results infer a role of material properties during morphogenesis and the approach paves the way for quantitative material investigations in vivo of embryos, explants, or organoids.

The Vascular Niche for Adult Cardiac Progenitor Cells.

Research on cardiac progenitor cell populations has generated expectations about their potential for cardiac regeneration capacity after acute myocardial infarction and during physiological aging; however, the endogenous capacity of the adult mammalian heart is limited. The modest efficacy of exogenous cell-based treatments can guide the development of new approaches that, alone or in combination, can be applied to boost clinical efficacy. The identification and manipulation of the adult stem cell environment, termed niche, will be critical for providing new evidence on adult stem cell populations and improving stem-cell-based therapies. Here, we review and discuss the state of our understanding of the interaction of adult cardiac progenitor cells with other cardiac cell populations, with a focus on the description of the B-CPC progenitor population (Bmi1+ cardiac progenitor cell), which is a strong candidate progenitor for all main cardiac cell lineages, both in the steady state and after cardiac damage. The set of all interactions should be able to define the vascular cardiac stem cell niche, which is associated with low oxidative stress domains in vasculature, and whose manipulation would offer new hope in the cardiac regeneration field.

On vasa vasorum: A history of advances in understanding the vessels of vessels.

The vasa vasorum are a vital microvascular network supporting the outer wall of larger blood vessels. Although these dynamic microvessels have been studied for centuries, the importance and impact of their functions in vascular health and disease are not yet fully realized. There is now rich knowledge regarding what local progenitor cell populations comprise and cohabitate with the vasa vasorum and how they might contribute to physiological and pathological changes in the network or its expansion via angiogenesis or vasculogenesis. Evidence of whether vasa vasorum remodeling incites or governs disease progression or is a consequence of cardiovascular pathologies remains limited. Recent advances in vasa vasorum imaging for understanding cardiovascular disease severity and pathophysiology open the door for theranostic opportunities. Approaches that strive to control angiogenesis and vasculogenesis potentiate mitigation of vasa vasorum–mediated contributions to cardiovascular diseases and emerging diseases involving the microcirculation.

An Airway-Centric View of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the cumulative manifestation of countless, spatially and temporally distinct, microscopic foci of maladaptive repair in response to recurrent lung injury. However, the key drivers, essential cells, and critical mechanisms of maladaptive repair in IPF remain elusive. Decades of research have focused on alveolar injury and alveolar-mesenchymal crosstalk with their association to type II alveolar epithelial defects, fibroblast activation, and progressive lung fibrosis resulting in diminished organ function. Additionally, it has been well documented that immune and endothelial cell-types are involved in IPF. However, the airway epithelium has been incompletely described in IPF, even with significant evidence of airway-specific involvement. One of the first descriptions of distal airway dysfunction in IPF was over four-decades ago; however, since this discovery, our understanding of distal airway epithelial contributions to IPF pathogenesis has not kept pace with other tissues-types or anatomical regions of the lung. Healthy distal, which is defined here as an airway < 2 mm in internal diameter, airway epithelium is composed primarily of progenitor, mucus-producing, and multiciliated cell populations. Large increases in progenitor population diversity, misexpression of mucus, and possible aberrant ciliation observed in IPF has reinvigorated interest in the distal airway epithelium.

Post natal expression of Prx1 labels appendicular restricted progenitor cell populations of multiple tissues.

Currently, there is no consensus whether there is a single or multiple postnatal stem cell population(s) that contribute to skeletal homeostasis and postnatal bone formation. A known population of cells that express Prx1 contributes to postnatal bone formation. Prx1 expression also connotes calvaria and appendicular tissues during embryonic development. A transgenic tamoxifen inducible Prx1 reporter mouse was used for lineage tracking, to characterize the postnatal contribution of Prx1 expressing cells in skeletal homeostasis and bone formation. Under homeostatic conditions Prx1 labeling gave rise to a transient yet rapid turnover cell population at the periosteal and endosteal surfaces, along muscle fibers, and within the medial layers of vessels both within the muscle and marrow compartments of the appendicular skeleton. Fracture and ectopic bone formation of both fore and hind limbs showed recruitment and expansion of Prx1-derived cells in newly formed bone tissues. Prx1 labeled cells were limited or absent at axial skeletal sites during both homeostasis and after induction of bone formation. Last, Prx1-derived cells differentiated into multiple cell lineages including vascular smooth muscle, adipose, cartilage, and bone cells. These results show that Prx1 expression retained its embryonic tissue specification and connotes a stem/progenitor cell populations of mesenchymal tissue progenitors.

Blast Waves Cause Immune System Dysfunction and Transient Bone Marrow Failure in a Mouse Model.

Explosive devices, either conventional or improvised, are common sources of injuries during combat, civil unrest, and terror attacks, resulting in trauma from exposure to blast. A blast wave (BW), a near-instantaneous rise in pressure followed by a negative pressure, propagates through the body in milliseconds and can affect physiology for days/months after exposure. Epidemiological data show that blast-related casualties result in significantly higher susceptibility to wound infections, suggesting long-lasting immune modulatory effects from blast exposure. The mechanisms involved in BW-induced immune changes are poorly understood. We evaluated the effects of BW on the immune system using an established murine model. Animals were exposed to BWs (using an Advanced Blast Simulator), followed by longitudinally sampling for 14 days. Blood, bone marrow, and spleen were analyzed for changes in the 1) complete blood count (CBC), and 2) composition of bone marrow cells (BMC) and splenocytes, and 3) concentrations of systemic cytokines/chemokines. Our data demonstrate that BW results in transient bone marrow failure and long-term changes in the frequency and profile of progenitor cell populations. Viability progressively decreased in hematopoietic stem cells and pluripotent progenitor cells. Significant decrease of CD4+ T cells in the spleen indicates reduced functionality of adaptive immune system. Dynamic changes in the concentrations of several cytokines and chemokines such as IL-1α and IL-17 occurred potentially contributing to dysregulation of immune response after trauma. This work lays the foundation for identifying the potential mechanisms behind BW’s immunosuppressive effects to inform the recognition of this compromised status is crucial for the development of therapeutic interventions for infections to reduce recovery time of wounded patients injured by explosive devices.

The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age.

Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopulations contribute to the dynamics of the reconstitution process and on whether and how these contributions are altered with age. In a murine model of HSCT, we therefore simultaneously tracked different cultivated and transduced hematopoietic stem and progenitor cell (HSPC) populations using a multicolor-coded barcode system (BC32). We studied a series of age-matched and age-mismatched transplantations and compared the influence of age on the reconstitution dynamics. We show that reconstitution from these cultured and assembled grafts was substantially driven by hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) independent of age. The reconstitution patterns were polyclonal and stable in all age groups independently of the variability between individual animals, with higher output rates from MPPs than from HSCs. Our experiments suggest that the dynamics of reconstitution and the contribution of cultured and individually transduced HSPC subpopulations are largely independent of age. Our findings support ongoing efforts to expand the application of HSCT in older individuals as a promising strategy to combat hematological diseases, including gene therapy applications.