Characterization of Spontaneous Bone Marrow Recovery after Sublethal Total Body Irradiation: Importance of the Osteoblastic/Adipocytic Balance

Abstract

Many studies have already examined the hematopoietic recovery after irradiation but paid with very little attention to the bone marrow microenvironment. Nonetheless previous studies in a murine model of reversible radio-induced bone marrow aplasia have shown a significant increase in alkaline phosphatase activity (ALP) prior to hematopoietic regeneration. This increase in ALP activity was not due to cell proliferation but could be attributed to modifications of the properties of mesenchymal stem cells (MSC). We thus undertook a study to assess the kinetics of the evolution of MSC correlated to their hematopoietic supportive capacities in mice treated with sub lethal total body irradiation. In our study, colony-forming units – fibroblasts (CFU-Fs) assay showed a significant MSC rate increase in irradiated bone marrows. CFU-Fs colonies still possessed differentiation capacities of MSC but colonies from mice sacrificed 3 days after irradiation displayed high rates of ALP activity and a transient increase in osteoblastic markers expression while pparγ and neuropilin-1 decreased. Hematopoietic supportive capacities of CFU-Fs were also modified: as compared to controls, irradiated CFU-Fs significantly increased the proliferation rate of hematopoietic precursors and accelerated the differentiation toward the granulocytic lineage. Our data provide the first evidence of the key role exerted by the balance between osteoblasts and adipocytes in spontaneous bone marrow regeneration. First, (pre)osteoblast differentiation from MSC stimulated hematopoietic precursor's proliferation and granulopoietic regeneration. Then, in a second time (pre)osteoblasts progressively disappeared in favour of adipocytic cells which down regulated the proliferation and granulocytic differentiation and then contributed to a return to pre-irradiation conditions.

Bone Marrow Regeneration Promoted by Biophysically Sorted Osteoprogenitors From Mesenchymal Stromal Cells

“…Similarly, other studies investigating the effects of irradiation or similar myeloablative procedures demonstrate that during BM recovery, the surviving perivascular MSCs proliferate and undergo a reversible and transient shift toward a state of higher osteogenic activity [19][20][21][22]. This was indicated by an increased expression of osteoblastic differentiation markers such as alkaline phosphatase, osteopontin, osteocalcin, and Runx2 (runtrelated transcription factor 2) during the recovery period [23].…”

Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase–expressing umbilical cord mesenchymal stromal cells

“…The radiation source used in the present studies used a137Cs-y source with a fixed exposure rate of 4.61 Gy/min (Sangyo Kagaku Co, Ltd). Because the device had a much higher irradi ation dose rate than those used in published reports [27][28][29][30][31][32][33][34][35], we conducted a pilot study to identify a dose that resulted in a 20% survival rate in mice at 2 weeks after exposure (Supplementary Figure S5). With the use of the a!37Cs-y source described, we determined that mice lived for only 6 days after the exposure dose reached 9 Gy; approximately 40% mice were alive 14 days after an exposure dose of 5.5 Gy, and 16.7% of the mice were alive at day 14 after a 6-Gy exposure dose.…”

The relationship between the alkaline phosphatase network and the haematopoiesis in mice subjected to whole-body irradiation

“…Secondly, if the bone marrow stromal cells, especially ALP--positive cells and/or their precursors, were seriously damaged in certain types of aplasia, then, the bone marrow may not be able to recover. In a recent study, a hypothesis has been put forward that the osteoblast lineage (ALP-positive cells) after irradiation engages in a reversible way and returns to a less differentiated stage [20]. We think that further studies, for example, the analysis of the ALP gene expression after irradiation, are needed to fully understand this issue.…”