What is the link between “Inflammation” and “Regenerative Medicine”? In this review series, we invited contributions from 5 outstanding groups of Japanese scientists. Two reviews by a distinguished group at Keio University elucidated new indicators for somatic stem cells within a bone marrow (BM) environment, with a particular focus on meschenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), respectively. The group of Drs. Mabuchi and Matsuzaki established a new definition for mouse and human MSCs by identifying new surface markers, which also exhibit the essential properties, self-renewal activity and multi-potency, of “stem cells”. MSCs show multifunctional diversity in regeneration and immunity, and have recently been strongly implicated in providing a novel “niche” for maintaining HSCs.

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Mesenchymal stem cells (MSCs) are currently defined as cells that undergo sustained in vitro growth and can give rise to multiple mesenchymal lineages. Traditional MSCs isolation methods require prolonged in vitro culture on plastic plates, which reduces their differentiation potential and proliferative ability. Furthermore, this process alters MSCs-phenotype, making it difficult to identify specific MSCs-markers that could be used for their in vivo localization and prospective isolation. These limitations have hindered investigations into the biology and function of MSCs. This review article focuses on recent developments in the MSC-research field including the identification of novel surface markers for the prospective isolation of both murine and human MSCs. Prospectively isolated MSCs are more proliferative than MSCs prepared by conventional plastic adherence, provide a better substrate for studying MSCs biology and have more potential for regenerative therapy.

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The interactions of stem cells with their supportive microenvironmental niches are mediated by signaling networks that control the balance between cellular self-renewal and differentiation. In hematopoietic stem cells (HSCs), the bone marrow (BM) supports both of these processes within specialized niches, namely, osteoblastic and perivascular niche, which contain supportive cellular and non-cellular elements. This review discusses HSC niches and niche cell populations, focusing on the osteoblastic niche cells in three fractions: osteoblast-enriched ALCAM⁺Sca-1^- and ALCAM^-Sca-1^-, and immature mesenchymal cell-enriched ALCAM^-Sca-1⁺ cells. Gene expression profiling showed that the ALCAM^-Sca-1⁺ fraction highly expressed cytokine-related genes whereas in the ALCAM⁺Sca-1^- fraction the predominantly expressed genes were those related to cell adhesion. In addition, by using single-cell gene expression analysis, we identified an osteoblastic marker^low/- subpopulation in ALCAM⁺Sca-1^- cells, which includes cells that express relatively high levels of pluripotent markers. Together, these findings indicate that multiple cell populations cooperatively support HSCs in the osteoblastic niche. Understanding the niche signals that regulate HSC maintenance and terminal differentiation could provide the basis for niche-based therapies that protect HSCs from various stresses and promote the ex vivo expansion of HSCs.

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We recently identified angiopoietin-like protein ANGPTL2 as a key mediator of chronic inflammation and its-associated diseases, such as obesity-related metabolic syndrome, cardiovascular disease, and some autoimmune diseases. Inflammation is receiving much attention for the role it plays at different stages of cancer development, including carcinogenesis, tumor invasion, and metastasis. More recently, we demonstrated that ANGPTL2 functions in the pathogenesis of cancer development, particular in inflammatory carcinogenesis and tumor metastasis. In this review, we focus on ANGPTL2 and its-associated chronic inflammation in carcinogenesis and tumor metastasis and propose that ANGPTL2 could serve a molecular target to prevent and treat pathologies associated with cancer.

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Obesity induces adipose tissue inflammation, but little is known about the interrelationships among immune cells. Therefore, to assess the dynamic interplay between multiple cell types in obese adipose, an in vivo visualization technique was developed. In vivo imaging revealed close spatial and temporal interrelationships between angiogenesis and adipogenesis, which were augmented in obese adipose tissue. In addition, increased leukocyte-platelet-endothelial cell interactions were observed in the microcirculation, a hallmark of inflammation. Upregulated expression of adhesion molecules contribute to local activation of inflammatory processes. We also found that large numbers of CD8+ effector T cells infiltrated into the obese adipose tissue, playing major roles in inflammatory macrophage infiltration into obese adipose tissue, induction and maintenance of inflammation, and systemic insulin resistance. Our results demonstrate the power of our imaging technique to analyze multi-cellular interactions in inflammation in vivo and to evaluate new therapeutic interventions.

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Induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine and other clinical applications, such as cell therapies, drug screening, toxicology testing, and the investigation of disease mechanisms. Discovery of disease-associated iPSCs has led to the development of a new field of disease modeling, as they can provide somatic cells which cannot be directly obtained from each patient. In this review, we focus on the applications of disease-associated iPSCs for understanding human hematological and immunological disorders, while discussing the current state of hematopoietic differentiation and the findings of previous reports of disease-associated iPSCs in this field.

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