Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients.
Bone marrow transplant (BMT) relies on the engraftment of donor hemopoietic precursors in the host marrow space. Colony forming units-fibroblasts (CFU-f), the precursor compartment for the osteogenic lineage, are essential to hemopoietic stem cell survival, proliferation and differentiation. We have studied CFU-f in donors (aged 5 months to 62 years) and in patients who had received allogeneic BMT (aged 2 months to 63 years). In donor marrows we found an inverse correlation between CFU-f frequency and age. In BMT recipients CFU-f frequencies were reduced by 60%-90% (p < 0.05) and the numbers did not recover up to 12 years after transplant. Stromal reconstitution to normal levels was found only in patients < 5 years old. In all patients studied CFU-f post-BMT were of host origin. Patients with low CFU-f levels displayed also a decreased bone mineral density (p < 0.05) and significantly reduced levels of long-term culture-initiating cells (LTC-IC) (p < 0.05). Our study demonstrates that the marrow stromal microenvironment is seriously and irreversibly damaged after BMT. Donor cells do not contribute to reconstitute the marrow microenvironment, whose residual CFU-fs remain of host origin.
Galotto
M
M
Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Berisso
G
G
Delfino
L
L
Podesta
M
M
Ottaggio
L
L
Dallorso
S
S
Dufour
C
C
Ferrara
G B
GB
Abbondandolo
A
A
Dini
G
G
Bacigalupo
A
A
Cancedda
R
R
Quarto
R
R
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology; D015519:Bone Density / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000473:pathology*; D016723:Bone Remodeling / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D030342:Genetic Diseases, Inborn / Q000628:therapy; D019337:Hematologic Neoplasms / Q000628:therapy; D006410:Hematopoiesis; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011832:Radiation Injuries / Q000473:pathology*; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D013852:Thiotepa / Q000008:administration & dosage / Q000009:adverse effects*; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D003520:Cyclophosphamide; D013852:Thiotepa