Elsevier

The Lancet

Volume 361, Issue 9363, 29 March 2003, Pages 1084-1088
The Lancet

Articles
Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study

https://doi.org/10.1016/S0140-6736(03)12894-2Get rights and content

Summary

Background

Adult bone marrow-derived (BMD) cells could be used to repair damaged organs and tissues, but the intrinsic plasticity of these cells has been questioned by results of in-vitro studies suggesting that such cells might fuse with other cells giving the appearance of differentiation. We aimed to determine whether fusion events are important in vivo.

Methods

To test whether BMD cells can colonise an epithelial tissue and differentiate there without fusion, we did in-situ hybridisation with Y and X chromosome probes labelled with 35-sulphur or digoxigenin, or labelled fluorescently. We did immunohistochemistry with anticytokeratin 13 along with fluorescence in-situ hybridisation to identify Y-chromosome positive buccal epithelial cells in cheek scrapings obtained from five females who had received either a bone-marrow transplant or an allogeneic mobilised peripheral-blood progenitor-cell transplant (enriched in CD34+ cells) from male donors.

Findings

When examined 4–6 years after male-to-female marrow-cell transplantation, all female recipients had Y-chromosome-positive buccal cells (0·8–12·7%). In more than 9700 cells studied, we detected only one XXXY-positive cell (0·01%) and one XXY cell (0·01%), both of which could have arisen when an XY cell fused with an XX cell.

Interpretation

Male BMD cells migrate into the cheek and differentiate into epithelial cells, an occurrence that does not depend on fusion of BMD cells to recipient cells. This finding might be an example of transdifferentiation of haemopoietic or stromal progenitor cells. Plasticity of BMD cells could be useful in regenerative medicine.

Introduction

Evidence from studies in recipients of bone-marrow transplants shows that bone marrow-derived (BMD) cells can differentiate into cells other than blood. This occurrence is of importance because such cells could be used to regenerate organs after disease or trauma.1, 2, 3, 4, 5 However, the plasticity of BMD cells has been questioned by results of studies suggesting that stem cells might fuse with other cells and give the appearance of differentiation.6, 7 Furthermore, caution is needed in interpretation of data purporting to show that non-haemopoietic cells are derived from donor BMD cells.8, 9, 10 Tissues, especially when affected by graft-versus-host disease (GVHD), might contain infiltrating donor haemopoietic or lymphoid cells. In histological sections, non-haemopoietic tissue cells might be confounded with haemopoietic cells because of cell overlap (attributable to the thickness of the sections) or loss of haemopoietic lineage-specific markers.

We aimed to establish whether BMD cells differentiate into cells of another tissue lineage, and to assess whether this event is attributable to fusion. To avoid contamination of our samples by haemopoietic inflammatory cells, we did our studies on healthy transplant recipients without oral GVHD, several years after bone-marrow transplantation.

Section snippets

Patients

Bone-marrow stem-cell transplant recipients residing within the USA, who each had received an allogeneic transplant from a male sibling donor through protocols from the National Heart, Lung, and Blood Institute, were invited to participate in the study. All those who agreed to participate were well, in haematological remission, with full donor lymphohaemopoietic engraftment and no active oral GVHD. The transplants these patients had received consisted of at least 3·106 CD34+ cells/kg and a

Results

Five females, 4–6 years after receiving a transplant from an HLA-identical brother for leukaemia, agreed to participate (table 1). Recipients 1, 2, 3, and 5 underwent a myeloablative conditioning regimen consisting of 4 days of total body irradiation (13·6 Gy) and 2 days of cyclophosphamide 60 mg/kg. Recipient 4 received the same dose of cyclophosphamide plus fludarabine 125 mg/m2 over 5 days. GVHD developed in four: acute grade 1 in recipient 1; chronic liver GVHD in recipient 3; extensive

Discussion

These results indicate that cells derived from marrow or granulocyte-colony stimulating factor mobilised blood cells migrate into the cheek and differentiate into epithelial cells. These results might therefore represent transdifferentiation of haemopoietic or stromal stem cells, or transplantation of a hypothetical epithelial progenitor cell.

Four criteria have been proposed to show plasticity of adult stem cells.14, 15 The first criterion states that cells grafted should be clonal. Our study

References (18)

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