New Bone Formation by Allogeneic Mesenchymal Stem Cell Transplantation in a Patient with Perinatal Hypophosphatasia

ABSTRACT:We examined the presence of circulating plastic adherent multipotent mesenchymal stem cells (MSCs) in fracture patients. Three patient groups (n = 10-18) were evaluated, including elderly females with a femoral neck fracture treated with cemented hemiarthroplasty, an age-and sex-matched group with hip osteoarthritis (OA) treated with cemented total hip arthroplasty (THA), and younger adults with surgically treated lower extremity fractures. The presence of circulating MSCs pre-and postoperatively was compared to bone marrow (BM) MSCs from the same subjects. Criteria for identifying MSCs included cell surface markers (CD105+, CD73+, CD90+, CD45−, CD14−), proliferation through several passages as well as osteogenic, chondrogenic, and adipogenic differentiation. Plastic adherent MSCs were found in peripheral blood (PB) from 22% of hip fracture patients, 46% of younger fracture patients, and in none of 63 pre-and postmenopausal women with hip OA. When detectable, circulating MSCs appeared between 39 and 101 h after fracture. PB derived MSCs did not differ from BM derived MSCs, except for a small population (<15%) of CD34+ cells among PB derived MSCs. This initial study indicates mobilization of MSCs into the circulation in response to fracture, even in very old patients, while circulating MSCs were not detectable before or after elective THA.

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“…[2][3][4][5][6][7]15 However, the significance and functional role of systemically recruited MSCs in fracture healing remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients

Alm

Koivu

Heino

et al. 2010

Journal Orthopaedic Research

108

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“…21,22 In hypophosphatasia, allogeneic bone marrow and/or MSC transplantation therapy has been reported by us and other groups. 4,14,23 However, the disease was not curable with these allo-transplantation therapies. In addition to the possible immunological rejection, allotransplantation is associated with some problems, such as infection and lack of appropriate donors.…”

Section: Discussionmentioning

confidence: 99%

“…DNA sequence analysis revealed that the patient has a heterozygous mutation in TNSALP gene: 1348CoT (R433C) and 1559delT. 14 It was reported that ALP protein with 1559delT mutation locates in cytoplasm 25 but the protein with R433C mutation appears to localize on the cellular membrane. 26 As we could detect the cell surface expression of ALP by flow cytometric analysis, cascades of transcription followed by translation of the TNSALP gene and transportation of translational product to cellular membrane well occurred in the patient's cell.…”

Section: Discussionmentioning

confidence: 99%

Restoration of cellular function of mesenchymal stem cells from a hypophosphatasia patient

et al. 2009

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Mesenchymal stem cells (MSCs) can differentiate into multiple cell lineages and are used for regenerative treatments for a variety of diseases. However, the patient's cells cannot be used to treat genetic diseases. Allogeneic cells can serve as an alternative but long-term survival is uncertain. Our experience of allo-transplantation to a patient with hypophosphatasia, which is caused by mutations of the tissue non-specific alkaline phosphatase (TNSALP) gene resulting in low serum alkaline phosphatase (ALP) activity and skeletal deformity, did not improve these clinical characteristics. Therefore, we sought to use autologous MSCs for the treatment of hypophosphatasia. MSCs derived from the patient's bone marrow had a similar profile when compared with well-reported MSCs. However, the MSCs had extremely low ALP activity and could not produce a mineralized bone matrix even under the osteogenic culture conditions. We therefore transduced a retroviral vector with TNSALP promoter-driven TNSALP gene in the MSCs. In the culture condition, the MSCs had about 7-fold higher ALP activity than did mock-transduced MSCs, and showed mineralization as well as bone-specific markers. Furthermore, the MSCs, but not mock-transduced MSCs, newly formed bone at the frequency of 50% in nude rats. Transplantation of the TNSALP-transduced autologous MSCs might become a new therapy for hypophosphatasia.

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“…8 Clinical studies of transplantation therapy for severe HPP have been conducted using allogeneic bone marrow cells (BMC), mesenchymal stem cells (MSC), and cultured osteoblasts. [9][10][11][12] The rationale of these protocols is that donor cells may distribute and engraft in the skeletal microenvironment to differentiate into osteoprogenitor cells synthesizing physiologically active TNALP. With these approaches, therapeutic benefits such as improved bone mineralization were observed, but the biochemical markers, including serum ALP activity, were not corrected.…”

mentioning

confidence: 99%

“…With these approaches, therapeutic benefits such as improved bone mineralization were observed, but the biochemical markers, including serum ALP activity, were not corrected. [9][10][11][12] Further studies aimed at further improving the therapeutic effect are thus needed.…”

mentioning

confidence: 99%

Prevention of Lethal Murine Hypophosphatasia by NeonatalEx VivoGene Therapy Using Lentivirally Transduced Bone Marrow Cells

et al. 2015

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New Bone Formation by Allogeneic Mesenchymal Stem Cell Transplantation in a Patient with Perinatal Hypophosphatasia

Cited by 64 publications

References 29 publications

Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients

Circulating plastic adherent mesenchymal stem cells in aged hip fracture patients

Restoration of cellular function of mesenchymal stem cells from a hypophosphatasia patient

Prevention of Lethal Murine Hypophosphatasia by NeonatalEx VivoGene Therapy Using Lentivirally Transduced Bone Marrow Cells

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