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Rebuilding of bone marrow niche after lethal irradiation

How is the bone marrow stem cell niche affected by irradiation? How it is rebuilding? Are niche cells coming from transplanted donor cells or recovering from the host? How can we play with it in therapeutic settings?

I was trying to find answers to these questions for quite long time and I’m going to share with you some interesting information and thoughts that I got from the literature.

The current general assumption in the field is that at least 2 distinct types of niches support hematopoietic stem cells (HSC) in bone marrow – vascular (endothelial) and osteoblastic (bone lining cells). Of course cellular interactions in bone marrow niche are more complex [1] and involve many cell types [2], but these 2 plus mesenchymal stem/progenitor cells are relatively well studied in experiments. I’ll focus on 3 major types of bone marrow niche cells – osteoblasts, mesenchymal (stromal) stem/progenitor cells (MSC) and endothelial (vascular) cells.

What is the niche cell response to radiation injury?
40 years ago, Metcalf group provided the evidence [3] that host bone-related radioresistant nonhematopoietic cells can support hematopoiesis better than control cells. Indeed, as was confirmed recently, host osteoblasts survive and reversibly expand after exposure to radiation [4].

Vascular component of bone marrow niche, unlike osteoblasts, is almost completely stripped out after lethal irradiation. Sinusoidal endothelial cells regressed severely and required complete rebuilding from donor marrow in order to sustain hematopoiesis [5].

Quiescent MSC in bone marrow stroma appear to be very resistant to whole-body lethal irradiation, but functionally defective [6] (impaired colony-forming ability in vitro).

Niche cells after bone marrow transplant – from host or from donor?
As I said above, osteoblasts are coming from the host and they are not a transplanted population within whole bone marrow, simply because these cells attach to the bone endosteal surface and don’t get into the aspirate when flushing from donor’s bone.

Donor MSC from whole marrow can give rise to both – vascular and osteoblastic cells types and even more – reticular SDF-1-positive cells and adipocytes. But donor MSC-derived osteoblasts can have limited regenerative contribution after transplantation [7] in favor of host-derived. Only about 7% or MSC engrafted and persist with time in irradiated bone marrow [6]. The rest of MSC is host-derived. Even only a little % of donor MSC contribute to rebuilding a niche, they seem to be very potent and significant for rescuing hematopoiesis.

It seem like endothelial niche should be derived from the donor marrow. Donor’s MSC and endothelial progenitors could be the source for rebuilding vascular niche. I don’t understand how the vascular niche is rebuilding right after transplant of purified HSC, but probably host MSC regenerate it eventually.

So, MSC can build virtually all hematopoietic niche cell types in bone marrow including a perivascular niche for themselves.

Clinical relevance
One of the major points of studying rebuilding a niche in bone marrow is increasing the engraftment of HSC and efficiency of bone marrow transplantation (BMT). Obviously, increasing niche recovery after meyloablative or non-ablative conditioning, can shorten time of HSC engratment and improve outcome of BMT.

1. It’s hard to translate finding in mice to human, because in BMT clinic some part of conditioning regimens (especially non-myeloablative) currently does not include total body irradiation. We don’t know how chemotherapy alone will affect the bone marrow niche. For example, chemotherapy without lethal irradiation did not destroy the vascular niche significantly [5] in mouse model. So, we have to study how different chemotherapeutical conditioning can affect a niche and how we can play with it. As a consequence, depends on clinical situation, we can choose myeloablative versus non-ablative protocol, with irradiation or without and what combination of chemotherapeutic drugs will favor HSC engraftment.

2. One of the important questions in BMT clinic is what graft to transplant – manipulated (fresh CD34+ sorted or enrich or cultured, T-cell depleted) or whole bone marrow? Based on the conclusions I noticed above, whole bone marrow (or just T-cell depleted) could be the best option, because there are niche cells in it and we should not get rid of them. Whether donor MSC can improve HSC engraftment in clinic needs to be determined [8]. it was demonstrate that MSC remain almost exclusively (96%) of host type, unlike hematopoietic cells [9] (100% from donor), irrespective of the conditioning regimen and graft source. So, unexpanded fresh donor MSC from the graft have no long-term direct contribution to rebuilding the niche, but paracrine mechanisms shouldn’t be ignored.

3. In leukemia settings it’s important to know whether total body irradiation will promote osteoblasts proliferation in favor of cancer stem cell expansion or not? Another question is whether fresh and healthy donor-derived niche cells completely or partially replace abnormal leukemic niche [10]? And if so, what preparative regimen should be used?