Crucial Role of Donor-Derived Stromal Cells in Successful Treatment for Intractable Autoimmune Diseases in MRL/lpr Mice by BMT Via Portal Vein

Authors

  • Taketoshi Kushida,

    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Department of Orthopedic Surgery, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Muneo Inaba,

    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Hiroko Hisha,

    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Naoya Ichioka,

    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Department of Orthopedic Surgery, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Takashi Esumi,

    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Department of Orthopedic Surgery, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Ryokei Ogawa,

    1. Department of Orthopedic Surgery, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Hirokazu Iida,

    1. Department of Orthopedic Surgery, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan
    Search for more papers by this author
  • Susumu Ikehara M.D., Ph.D.

    Corresponding author
    1. First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
    2. Transplantation Center, Kansai Medical University, Moriguchi City, Osaka, Japan
    • First Department of Pathology, Transplantation Center, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan. Telephone: 81-6-6993-9429; Fax: 81-6-6994-8283
    Search for more papers by this author

Abstract

We have recently established a new bone marrow transplantation (BMT) method for the treatment of intractable autoimmune diseases in MRL/lpr mice; the method consists of fractionated irradiation (5.5 Gy × 2), followed by BMT of whole bone marrow cells (BMCs) from allogeneic C57BL/6 mice via the portal vein (abbreviated as 5.5 Gy × 2 + PV). In the present study, we investigate the mechanisms underlying the early engraftment of donor-derived cells in MRL/lpr mice by this method. In the mice treated with this method, the number of donor-derived cells possessing the mature lineage (Lin) markers rapidly increased in the BM, spleen, and liver; almost 100% were donor-derived cells by 14 days after the treatment. The number of donor-derived hemopoietic progenitor cells (defined as c-kit+/Lin cells) increased in the BMCs, hepatic mononuclear cells, and especially spleen cells by 14 days after the treatment. Simultaneously, hemopoietic foci adjoining donor-derived stromal cells were observed in the liver when injected via the PV, but not via the peripheral vein (i.v.). When adherent cell-depleted BMCs were injected via the PV, recipients showed a marked reduction in the survival rate. However, when mice were transplanted with adherent cell-depleted BMCs with cultured stromal cells, all the recipients survived.

These findings suggest that not only donor hematopoietic stem cells (HSCs) but also donor stromal cells administered via the PV were trapped in the liver, resulting in the early engraftment of donor HSCs in cooperation with donor-derived stromal cells. This new strategy to facilitate the early recovery of hemopoiesis would therefore be of great advantage in human application.

Ancillary