Bone marrow fibroblasts were originally thought to be those cells supporting the homing and proliferation of hematopoietic cells (Friedenstein et al. 1982). Continuous bone marrow cultures provided a system by which to study cells of the hematopoietic microenvironment and their interaction with hematopoietic stem cells in vitro (Dexter et al. 1977). Hematopoietic stem cells derived from long-term bone marrow culture were shown to have the properties of freshly derived stem cells from donor mice (Dexter et al. 1977). Hematopoietic reconstitution of lethally irradiated mice by transplant of stem cells derived from long-term bone marrow cultures that had been in vitro for months, demonstrated the capacity of an in vitro culture system to contain persistent totipotential stem cells. Within the hematopoietic niche of these marrow cultures “cobblestone islands” were shown to contain quiescent cells that harbored true stem cells (Greenberger 1978; Mauch et al. 1980; Sakakeeny and Greenberger 1982). The aging of continuous bone marrow cultures was associated with decline in the number of stem cells and production of committed hematopoietic progenitors (Sakakeeny and Greenberger 1982). The long-term bone marrow culture system remains the only in vitro system for maintenance of true stem cells outside the body for long durations (Sakakeeny and Greenberger 1982).

Other organ explant systems have been shown to share some properties of the long-term bone marrow culture system (Kataoka et al. 2003; Kalabis et al. 2008; Engelhardt et al. 1993). The success of the long-term bone marrow culture system allowed focus on those cells of the microenvironment (nonhematopoietic) which were responsible for stable quiescence of hematopoietic stem cells (Mauch et al. 1980). Following explant to culture, long-term marrow cultures were shown to contain cells with endothelial markers, fibroblast markers, as well as macrophage markers (Sakakeeny and Greenberger 1982). The hematopoietic microenvironment was thought to be composed of these three cell types (Dexter et al. 1977). Accumulation of neutral fat/lipid in bone marrow stromal cell association of lipid containing droplets in stromal cells near hematopoietic niches, suggested that the adipocyte was the critical hemopoiesis supporting stromal cell (Greenberger 1978). Further information indicated that lipid accumulation was in fact the toxic response of bone marrow to the high concentrations of fat and corticosteroid in horse serum used to establish the cultures (Greenberger 1978). Cultures with limited fat accumulation led to longer duration of hematopoiesis (Sakakeeny and Greenberger 1982). This data was consistent with the clinical observation that accumulation of yellow fat occurs in bone marrow during aging, and the fatty repopulation of the marrow microenvironment was associated with hematopoietic failure (Sakakeeny and Greenberger 1982).

Ionizing irradiation effects on the hematopoietic microenvironment were shown to be similar to those in natural aging (Zhou et al. 2008). Irradiated cells accumulated fat more quickly (Greenberger 1991), irradiated cells in culture showed upregulation of p53 and p21, stress response elements also shown to be upregulated during aging of bone marrow stromal cells (Zhou et al. 2008). Factors which reversed fat accumulation and aging effects in bone marrow stromal cells were shown to enhance hematopoiesis (Lechpammer et al. 2005; Epperly et al. 2007).

There is evidence that the cells of bone marrow microenvironment can be repopulated/replenished by cells of donor bone marrow origin (Anklesaria et al. 1989; Werts et al. 1980). Replacement of the microenvironment was first demonstrated by Werts and Degowin (Werts et al. 1980) and confirmed by Anklesaria et al. (1989) who showed that bone marrow stromal cells engrafted less effectively to high dose irradiated sites compared to low dose irradiated sites. These cells were called bone marrow fibroblasts, but later were shown to be those cells capable of multilineage differentiation (Pittenger et al. 1999).

Bone marrow stromal cells can engraft into a fracture/bone wound healing defect in vivo (Gokhale et al. 2010) and they are involved in regeneration/osteogenesis in irradiation damage tissue. Higher irradiation doses limit the capacity of migratory cells to be involved in bone healing (Gokhale et al. 2010). Antioxidant administration facilitates improved mesenchymal stem cell engraftment. However, serious negative effect of bone marrow stromal cell engraftment is the role of these cells in late tissue irradiation damage. Bone marrow stromal cells have been shown to contribute significantly to the fibrosis in irradiated lung (Epperly et al. 2003). Bone marrow stromal cell involvement in fibrosis is also a factor in chemotherapeutic drug induced lung damage such as that by bleomycin injury (Ortiz et al. 2003). Under one set of conditions, bone marrow-derived cells can be involved in tissue repair and potentially organ reconstitution, and under another set of conditions a distinct mesenchymal stem cell subset can contribute to late fibrotic damage which limits organ recovery. The subtle dynamics of cell migration into an irradiated microenvironment can be either beneficial or deleterious depending on the cell population and the timing.

It is clear that above a toxic threshold dose of irradiation (which may differ between tissues and organs) spontaneous tissue reconstitution may not follow. The protection or replacement by bone marrow cells of the irradiation damaged tissue microenvironment after such a toxic dose may lead to improved tissue recovery. There is controversy as to whether the microenvironment for stem cells is in fact a vascular space (Lombaert et al. 2008) or a specific cell type which functions as the niche (Anklesaria et al. 1989; Adams et al. 2007; Zhang et al. 2003). There is further controversy over whether the cells of the microenvironment as well as the stem cell population itself can be replaced by bone marrow.

Reconstitution of irradiated epithelial and nonepithelial tissues is dependent upon a subtle interplay between migratory beneficial cells (tissue reparative stem cells) and deleterious late damage inducing cells (fibrosis inducing mesenchymal stem cells). One approach toward tipping the balance toward repair may be to limit oxidative stress responses in the irradiated tissue microenvironment which change the makeup of cytokine production and release. Therefore, in addition to marrow-derived stem cell transplant, local delivery of antioxidants by stimulation of the in situ replenishment of antioxidant stores, by specific antioxidant diets, or by direct perfusion with antioxidants may facilitate tissue repair. Research is ongoing and important to achieve the goal of replacing irradiation-damaged tissue through donor stem cell transplantation.