Hematopoietic stem cell origin of human fibroblasts: cell culture studies of female recipients of gender-mismatched stem cell transplantation and patients with chronic myelogenous leukemia.
OBJECTIVE
Our series of studies using transplantation of single hematopoietic stem cells (HSCs) demonstrated that mouse fibroblasts/myofibroblasts are derived from HSCs. In order to determine the origin of human fibroblasts, we established a method for culturing fibroblasts from human peripheral blood (PB) mononuclear cells and studied fibroblasts from gender-mismatched HSC transplant recipients and patients with untreated Philadelphia chromosome-positive chronic myelogenous leukemia (CML).


METHODS
We cultured PB cells from three female subjects who showed near-complete hematopoietic reconstitution from transplantation of granulocyte-colony stimulating factor-mobilized male PB cells and examined the resulting fibroblasts using fluorescent in situ hybridization for Y chromosome. Because the mobilized PB cells may contain mesenchymal stem cells, we could not determine the HSC or mesenchymal stem cell origin of the fibroblasts seen in culture. To further document the HSC origin of human fibroblasts, we next examined fibroblasts from two patients with untreated CML, a known clonal disorder of HSCs.


RESULTS
All cultured fibroblasts from female recipients of male cells showed the presence of Y chromosome, indicating the donor origin of fibroblasts. Cultured fibroblasts from the CML patients revealed the presence of BCR-ABL translocation. This demonstration provided strong evidence for the HSC origin of human fibroblasts because CML is a clonal disorder of the HSC.


CONCLUSIONS
These studies strongly suggest that human fibroblasts are derived from HSCs. In addition, the results suggest that fibrosis seen in patients with CML may be a part of the clonal process.
Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Keisuke
K
Shirai
Yasuhiko
Y
Sera
William
W
Bulkeley
Meenal
M
Mehrotra
Omar
O
Moussa
Amanda C
AC
LaRue
Dennis K
DK
Watson
Robert K
RK
Stuart
John
J
Lazarchick
Makio
M
Ogawa
D000199:Actins / Q000032:analysis; D019070:Cell Lineage; D002478:Cells, Cultured; D041321:Chromosomes, Human, X / Q000235:genetics; D041322:Chromosomes, Human, Y / Q000235:genetics; D024042:Collagen Type I / Q000032:analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000473:pathology / Q000601:surgery; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000199:Actins; D024042:Collagen Type I; D016044:Fusion Proteins, bcr-abl