Healthcare resource utilisation and sickness absence in newly diagnosed multiple myeloma patients who did not undergo autologous stem cell transplantation: Trends in Sweden with the changing treatment landscape.

OBJECTIVES: The introduction of novel drugs has significantly improved outcomes for multiple myeloma (MM) patients. This study describes survival, healthcare resource utilisation and sickness absence in association with the changing MM treatment landscape over time, focussing on patients who did not undergo autologous stem cell transplantation (ASCT). METHODS: Population-based, retrospective registry study in Sweden, where 7012 non-ASCT patients diagnosed between 2001 and 2015 were stratified into diagnosis periods 2001-2005 (n = 2053), 2006-2010 (n = 2372) and 2011-2015 (n = 2587). RESULTS: Median survival increased from 2.5 to 3.4 years from 2001-2005 to 2011-2015. During the first 3 years of follow-up, patients diagnosed during 2011-2015 spent 29% and 12% less time in health care (55 days; inpatient admissions and outpatient visits) than patients diagnosed during 2001-2005 (78 days) and 2006-2010 (63 days), respectively. This was associated with less inpatient and more outpatient healthcare usage. Average 3-year sickness absence (362 days) was 31% and 12% less than for patients diagnosed during 2001-2005 (522 days) and 2006-2010 (410 days), respectively. CONCLUSIONS: These findings of improved survival, reduced healthcare needs and greater productivity in non-ASCT MM patients with access to improved treatment practices and novel drugs provide important real-world cost-benefit insights for the continued development and introduction of treatments for MM.

Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis.

Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute ∼10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects.

The effect of CSF-1 administration on lung maturation in a mouse model of neonatal hyperoxia exposure.

BACKGROUND: Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration. METHODS: Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 µg/g, daily × 5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry. RESULTS AND DISCUSSION: Seven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp + PBS and Hyp + CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp + PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp + PBS and Hyp + CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an exacerbation of lung injury. The trophic functions of macrophages in lung development requires further elucidation in order to explore macrophage modulation as a strategy for promoting lung maturation.

Macrophages and CSF-1: implications for development and beyond.

Recent focus on the diversity of macrophage phenotype and function signifies that these trophic cells are no longer of exclusive interest to the field of immunology. As key orchestrators of organogenesis, the contribution of macrophages to fetal development is worthy of greater attention. This review summarizes the key functions of macrophages and their primary regulator, colony-stimulating factor (CSF)-1, during development; highlighting trophic mechanisms beyond phagocytosis and outlining their roles in a range of developing organ systems. Advances in the understanding of macrophage polarization and functional heterogeneity are discussed from a developmental perspective. In addition, this review highlights the relevance of CSF-1 as a pleiotropic developmental growth factor and summarizes recent experimental evidence and clinical advancements in the area of CSF-1 and macrophage manipulation in reproduction and organogenic settings. Interrogation of embryonic macrophages also has implications beyond development, with recent attention focused on yolk sac macrophage ontogeny and their role in homeostasis and mediating tissue regeneration. The regulatory networks that govern development involve a complex range of growth factors, signaling pathways and transcriptional regulators arising from epithelial, mesenchymal and stromal origins. A component of the organogenic milieu common to the majority of developing organs is the tissue macrophage. These hemopoietic cells are part of the mononuclear phagocyte system regulated primarily by colony-stimulating factor (CSF)-1 (1, 2). There is a resurgence in the field of CSF-1 and macrophage biology; where greater understanding of the heterogeneity of these cells is revealing contributions to tissue repair and regeneration beyond the phagocytic and inflammatory functions for which they were traditionally ascribed (3-6). The accumulation of macrophages during tissue injury is no longer viewed as simply a surrogate for disease severity, with macrophages now known to be vital in governing tissue regeneration in many settings (7-11). In particular it is the influence of CSF-1 in regulating an alternative macrophage activation state that is increasingly linked to organ repair in a range of disease models (12-17). With many similarities drawn between organogenesis and regeneration, it is pertinent to re-examine the role of CSF-1 and macrophages in organ development.

M2 macrophage polarisation is associated with alveolar formation during postnatal lung development.

BACKGROUND: Macrophages are traditionally associated with inflammation and host defence, however a greater understanding of macrophage heterogeneity is revealing their essential roles in non-immune functions such as development, homeostasis and regeneration. In organs including the brain, kidney, mammary gland and pancreas, macrophages reside in large numbers and provide essential regulatory functions that shape organ development and maturation. However, the role of macrophages in lung development and the potential implications of macrophage modulation in the promotion of lung maturation have not yet been ascertained. METHODS: Embryonic day (E)12.5 mouse lungs were cultured as explants and macrophages associated with branching morphogenesis were visualised by wholemount immunofluorescence microscopy. Postnatal lung development and the correlation with macrophage number and phenotype were examined using Colony-stimulating factor-1 receptor-enhanced green fluorescent protein (Csf1r-EGFP) reporter mice. Structural histological examination was complemented with whole-body plethysmography assessment of postnatal lung functional maturation over time.Flow cytometry, real-time (q)PCR and immunofluorescence microscopy were performed to characterise macrophage number, phenotype and localisation in the lung during postnatal development. To assess the impact of developmental macrophage modulation, CSF-1 was administered to neonatal mice at postnatal day (P)1, 2 and 3, and lung macrophage number and phenotype were assessed at P5. EGFP transgene expression and in situ hybridisation was performed to assess CSF-1R location in the developing lung. RESULTS: Macrophages in embryonic lungs were abundant and densely located within branch points during branching morphogenesis. During postnatal development, structural and functional maturation of the lung was associated with an increase in lung macrophage number. In particular, the period of alveolarisation from P14-21 was associated with increased number of Csf1r-EGFP+ macrophages and upregulated expression of Arginase 1 (Arg1), Mannose receptor 1 (Mrc1) and Chemokine C-C motif ligand 17 (Ccl17), indicative of an M2 or tissue remodelling macrophage phenotype. Administration of CSF-1 to neonatal mice increased trophic macrophages during development and was associated with increased expression of the M2-associated gene Found in inflammatory zone (Fizz)1 and the growth regulator Insulin-like growth factor (Igf)1. The effects of CSF-1 were identified as macrophage-mediated, as the CSF-1R was found to be exclusively expressed on interstitial myeloid cells. CONCLUSIONS: This study identifies the presence of CSF-1R+ M2-polarised macrophages localising to sites of branching morphogenesis and increasing in number during the alveolarisation stage of normal lung development. Improved understanding of the role of macrophages in lung developmental regulation has clinical relevance for addressing neonatal inflammatory perturbation of development and highlights macrophage modulation as a potential intervention to promote lung development.

The directed differentiation of human iPS cells into kidney podocytes.

The loss of glomerular podocytes is a key event in the progression of chronic kidney disease resulting in proteinuria and declining function. Podocytes are slow cycling cells that are considered terminally differentiated. Here we provide the first report of the directed differentiation of induced pluripotent stem (iPS) cells to generate kidney cells with podocyte features. The iPS-derived podocytes share a morphological phenotype analogous with cultured human podocytes. Following 10 days of directed differentiation, iPS podocytes had an up-regulated expression of mRNA and protein localization for podocyte markers including synaptopodin, nephrin and Wilm's tumour protein (WT1), combined with a down-regulation of the stem cell marker OCT3/4. In contrast to human podocytes that become quiescent in culture, iPS-derived cells maintain a proliferative capacity suggestive of a more immature phenotype. The transduction of iPS podocytes with fluorescent labeled-talin that were immunostained with podocin showed a cytoplasmic contractile response to angiotensin II (AII). A permeability assay provided functional evidence of albumin uptake in the cytoplasm of iPS podocytes comparable to human podocytes. Moreover, labeled iPS-derived podocytes were found to integrate into reaggregated metanephric kidney explants where they incorporated into developing glomeruli and co-expressed WT1. This study establishes the differentiation of iPS cells to kidney podocytes that will be useful for screening new treatments, understanding podocyte pathogenesis, and offering possibilities for regenerative medicine.

Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses.

Colony-stimulating factor (CSF)-1 controls the survival, proliferation, and differentiation of macrophages, which are recognized as scavengers and agents of the innate and the acquired immune systems. Because of their plasticity, macrophages are endowed with many other essential roles during development and tissue homeostasis. We present evidence that CSF-1 plays an important trophic role in postnatal organ growth and kidney repair. Notably, the injection of CSF-1 postnatally enhanced kidney weight and volume and was associated with increased numbers of tissue macrophages. Moreover, CSF-1 promotes postnatal renal repair in mice after ischemia-reperfusion injury by recruiting and influencing macrophages toward a reparative state. CSF-1 treatment rapidly accelerated renal repair with tubular epithelial cell replacement, attenuation of interstitial fibrosis, and functional recovery. Analysis of macrophages from CSF-1-treated kidneys showed increased expression of insulin-like growth factor-1 and anti-inflammatory genes that are known CSF-1 targets. Taken together, these data suggest that CSF-1 is important in kidney growth and the promotion of endogenous repair and resolution of inflammatory injury.