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IntroductionBone marrow (BM) stromal cells were first identified by Friedenstein, who described an adherent fibroblast-like population able to differentiate into bone that he referred to as osteogenic precursor cells. 1 Subsequent studies demonstrated that these cells have the ability to differentiate into various other mesodermal cell lineages, including chondrocytes, tenocytes, and myoblasts (reviewed in Prockop 2 ). Based on this multilineage differentiation capacity, Caplan introduced the term mesenchymal stem cells (MSCs), 3 although many other terms have been introduced to describe a nonhomogenous population of multipotent cells. Although MSCs at a population level fulfill stem-cell criteria (ie, self renewal and multilineage differentiation capacity), it remains questionable whether the qualification "stem cell" is legitimate for MSCs at the single cell level. It was therefore recently proposed to use the term multipotent mesenchymal stromal cells (with the acronym MSCs) to describe fibroblast-like plastic-adherent cells. 4 Recently, Bonnet et al demonstrated that single cell-derived populations of murine BM-derived MSCs characterized by stage-specific embryonic antigen-1 expression, were capable of differentiation in vivo, 5 thus showing their true stem-cell properties. In this review, we will refer to the multipotent mesenchymal stromal cells with the acronym MSCs.Although MSCs originally were isolated from BM, 6 similar populations have been isolated from other tissues, including adipose tissue, 7 placenta, 8 amniotic fluid, 9 and fetal tissues such as fetal lung and blood. 10 In addition, umbilical cord blood (UCB) has been identified as a source of MSCs. 11,12 Probably as a result of their low frequency in UCB, conflicting reports initially have been published on the presence of MSCs in UCB. It has now become clear that the volume and storage time of the cord blood are important parameters for successful isolation of MSCs from UCB. 11 At present no specific marker or combination of markers has been identified that specifically defines MSCs. Phenotypically, ex vivo expanded MSCs express a number of nonspecific markers, including CD105 (SH2 or endoglin), CD73 (SH3 or SH4), CD90, CD166, CD44, and CD29. 6,13 MSCs are devoid of hematopoietic and endothelial markers, such as CD11b, CD14, CD31, and CD45. 6 The capacity to differentiate into multiple mesenchymal lineages, including bone, fat, and cartilage, is being used as a functional criterion to define MSCs. 2 21 and recently in amniotic fluid. 22 These primitive cell types require specific and stringent culture conditions, including embryonic stem cell-specific fetal calf serum (FCS), coated culture dishes (a.o. fibronectin), medium with specific growth factor requirements, specific type or culture dish, and prolonged culture duration at low cell density. Culturing these cells at higher cell density promotes differentiation toward a mesenchymal progenitor cell with restricted differentiation potential. 23 It has not been possible to prospectively isolat...

In addition to their stem/progenitor properties, mesenchymal stromal cells (MSCs) possess broad immunoregulatory properties that are being investigated for potential clinical application in treating immune-based disorders. An informed view of the scope of this clinical potential will require a clear understanding of the dynamic interplay between MSCs and the innate and adaptive immune systems. In this Review, we outline current insights into the ways in which MSCs sense and control inflammation, highlighting the central role of macrophage polarization. We also draw attention to functional differences seen between vivo and in vitro contexts and between species. Finally, we discuss progress toward clinical application of MSCs, focusing on GvHD as a case study.

The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue-inducer cells (LTi cells) as lineage-negative RORC+ CD127+ cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro, LTi cells gave rise to RORC+ CD127+ NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell-like cells and RORC+ CD127+ NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-gamma. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the mdr1b gene [ mdr1b (−/−) mice] and in both the mdr1a and mdr1b genes [ mdr1a/1b (−/−) mice]. In spite of the host of functions speculatively attributed to the mdr1-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum–chemical, and immunological parameters were not abnormal in mdr1a/1b (−/−) mice. The high level of mdr1b P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically, mdr1a/1b (−/−) mice behaved similarly to the previously analyzed mdr1a (−/−) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of mdr1a/1b (−/−) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (−/−) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.