Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The vasculature is emerging as an important component of stem cell niches. Here, we show that the adult subventricular zone (SVZ) neural stem cell niche contains an extensive planar vascular plexus that has specialized properties. Dividing stem cells and their transit-amplifying progeny are tightly apposed to SVZ blood vessels both during homeostasis and regeneration. They frequently contact the vasculature at sites that lack astrocyte endfeet and pericyte coverage, a modification of the blood-brain barrier unique to the SVZ. Moreover, regeneration often occurs at these sites. Finally, we find that circulating small molecules in the blood enter the SVZ. Thus, the vasculature is a key component of the adult SVZ neural stem cell niche, with SVZ stem cells and transit-amplifying cells uniquely poised to receive spatial cues and regulatory signals from diverse elements of the vascular system.

Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4 ؉ and CD8 ؉ T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4 ؉ CD25 ؉ FoxP3 ؉ T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell-depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008). (Blood. 2012;120(24): 4882-4891) IntroductionDelays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection, relapse, and secondary malignancies. [1][2][3][4][5][6] The risk of opportunistic infections is correlated with T-cell recovery, and in particular CD4 ϩ T cells. 1,7 Strategies to enhance T-cell reconstitution may therefore decrease posttransplantation morbidity and mortality. IL-7 has a central role in T-cell development and survival, and it enhances thymopoiesis and peripheral T-cell survival and expansion in murine models of allo-HSCT. [8][9][10][11][12][13][14][15][16][17][18][19] Initial trials with recombinant human IL-7 (r-hIL-7) demonstrated an expansion of CD4 ϩ and CD8 ϩ T cells in patients with solid tumors or HIV infection. [20][21][22][23][24][25] We conducted a phase 1 trial of r-hIL-7 (CYT107, Cytheris Inc) in recipients of T cell-depleted (TCD) allo-HSCTs and showed that r-hIL-7 was well tolerated and induced a rapid increase in peripheral CD4 ϩ and CD8 ϩ T cells. Methods Patient populationPatients more than 15 years of age were in remission without active or prior GVHD 60-210 days after TCD allo-HSCT from an 8 of 8 HLA-matched donor for treatment of nonlymphoid hematologic malignancy. The timing interval of study entry was selected to allow for adequate engraftment and the absence of significant transplant-related complications, as well as the inclusion of patients with poor immune recovery at 6 months after HSCT (CD4 Ͻ 100/mm 3 ). Additional requirements included documented engraftment (sustained absolute neutrophil count Ͼ 1000/mm 3 , platelet count Ͼ 20 000/mm 3 ), Karnofsky performance status Ͼ 60, normal left ventricular...

The distinction between a benign subungual pigmented macule (lentigo) and an early lesion of melanoma in situ can be difficult. To identify histologic parameters of potential diagnostic value, we retrospectively reviewed biopsies and excisions of 35 pigmented nail lesions. We studied 20 melanomas (10 invasive and 10 noninvasive) and 15 benign subungual melanotic lentigines. Ten specimens of normal nail apparatus obtained for reasons other than melanonychia were also examined as controls. The parameters, which were analyzed, included the density of melanocytes, the presence of multinucleated cells, pagetoid spread, cytologic atypia, inflammation, and the distribution of melanin pigment. The density of melanocytes was measured as the number of cells per 1 mm stretch of subungual dermo-epithelial junction [=melanocyte count (MC)]. The MC for invasive melanomas was as follows: mean=102, median=92.5, and range 52 to 212. For noninvasive (only in situ) melanoma, the mean MC was 58.9, median 51, and range 39 to 136. For benign subungual melanotic macules, the mean MC was 15.3, median 14, and range 5 to 31. In normal controls, the mean MC was 7.7, median 7.5, and range 4 to 9. Qualitative features associated with in situ melanoma and useful for its distinction from benign subungual melanotic macules included the presence of confluent stretches of solitary units of melanocytes, multinucleated melanocytes, lichenoid inflammatory reaction, and florid pagetoid spread of melanocytes.

In mice, the transcription factor, PLZF, controls the development of effector functions in invariant NKT cells and a subset of NKT cell-like, γδ T cells. Here, we show that in human lymphocytes, in addition to invariant NKT cells, PLZF was also expressed in a large percentage of CD8+ and CD4+ T cells. Furthermore, PLZF was also found to be expressed in all γδ T cells and in all NK cells. Importantly, we show that in a donor lacking functional PLZF, all of these various lymphocyte populations were altered. Therefore, in contrast to mice, PLZF appears to control the development and/or function of a wide variety of human lymphocytes that represent more than 10% of the total PBMCs. Interestingly, the PLZF-expressing CD8+ T cell population was found to be expanded in the peripheral blood of patients with metastatic melanoma but was greatly diminished in patients with autoimmune disease.