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The characteristics of hematopoietic stem cells from autoimmune-prone mice and the role of neural cell adhesion molecules in abnormal proliferation of these cells in MRL/lpr mice

From the 1^st Dept. of Pathology (XW, HH, WC, CS, TM, SO, QL, WF, JK, SI); Regeneration Research Center for Intractable Diseases (HH, SI); Dept. of Transplantation for Regeneration Therapy (Sponsored by Otsuka Pharmaceutical Co., Ltd.) (HH, SI); Dept. of Microbiology (SJ) Kansai Medical Univ., Moriguchi City, Osaka, 570-8506, Japan; Dept. of Toxicology, School of Public Health, Jilin University, Changchun, Jilin, 130021, China (XW, HF).

Correspondence: Susumu Ikehara, MD, PhD, First Department of Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan. E-mail: ikehara{at}takii.kmu.ac.jp

Background and Objectives: Using various animal models for autoimmune diseases, we have previously shown that such diseases are stem cell disorders.¹ In order to understand how autoimmune diseases develop, we investigated the distinct qualitative differences between hematopoietic stem cells (HSC) from normal and autoimmune-prone mice.

Design and Methods: We studied the major histocompatibility complex (MHC) restriction between HSC and stromal cells in vitro and in vivo. We also examined the ability of HSC to adhere to a stromal cell line and, using flow cytometry, analyzed the expression of various adhesion molecules in HSC before and after the onset of autoimmune disease. In addition, the effect of antibodies to anti-adhesion molecules on the proliferation of HSC was investigated.

Results: The abnormal HSC of MRL/lpr mice showed no MHC restriction (or preference) with stromal cells either in vitro or in vivo, although there was MHC restriction between normal HSC and stromal cells, as we previously reported.^2,3 The abnormal HSC of MRL/lpr mice exhibited enhanced adhesion to stromal cells in vitro and expressed a higher amount of adhesion molecules such as neural cell adhesion molecule (NCAM). Interestingly, the proliferation of HSC in MRL/lpr mice was significantly suppressed by anti-NCAM monoclonaal antibodies.

Interpretation and Conclusions: Abnormal HSC of MRL/lpr mice are more resilient than normal HSC. Furthermore, among various adhesion molecules, only NCAM shows increased expression on HSC of MRL/lpr mice after the onset of autoimmune diseases, and these molecules contribute to the enhanced proliferation capacity of abnormal HSC in MRL/lpr mice. The present findings suggest that there are intrinsic qualitative differences between HSC from normal and autoimmune-prone MRL/lpr mice.

Key words: hematopoietic stem cells, MRL/lpr mice, bone marrow transplantation, NCAM.

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