Serial Transplantation and Long-term Engraftment of Intra-arterially Delivered Clonally Derived Mesenchymal Stem Cells to Injured Bone Marrow

Abstract

It has been hypothesized that mesenchymal stem cells (MSCs) home to sites of injury. Nevertheless, efficient delivery of MSCs to target organs and description of their ultimate fate remain major challenges. We provide evidence that intra-arterially (IA) injected MSCs selectively engraft from the circulation as perivascular cells in the bone marrow (BM) after a localized radiation injury. Luciferase-expressing MSCs, derived from a conditionally immortalized clone (BMC-9) representing a pure population of cells, were arterially delivered into mice irradiated in one leg. Cell distribution was measured by bioluminescent imaging and final destination assessed by luciferase immunolocalization. IA injections resulted in engraftment only in the irradiated leg where cells localize and proliferate abluminal to the BM vasculature, a phenomenon not replicated with intravenous injections or with IA injections of kidney cells harvested from the same donor used for MSCs. Furthermore, MSCs harvested from the engrafted marrow and serially transplanted retain the ability to selectively engraft at sites of injury. This study demonstrates that MSCs can serially engraft at sites of injury from the circulation, that they reside in the perivascular space, and that arterial delivery is more efficient than venous delivery for cell engraftment.

The MSC curtain that stops the immune system

“…This multipotency inferred that these cells were stem cells; others showed that clones of MSCs could form multiple mesenchymal phenotypes [3]. Recently, we showed that cells derived from a clone of MSCs could be serially implanted in a rodent marrow injury model, and that these cells would serially engraft in this marrow injury model, implying for hematologists that the MSCs were "stem" cells [11].…”

“…From the backs of the MSCs, they produce molecules that establish a zone of regeneration [17]. This zone involves: (1) stopping the formation of scar tissue, (2) inhibiting the apoptosis of cells due to the ischemia because of the broken blood vessels, (3) the stimulation of the formation and stabilization of new blood vessels [18], and (4) the secretion of trophic factors that cause the replication of tissue intrinsic progenitors [4,11,15,19]. I summarily refer to these four activities as providing a trophic milieu [4].…”

“…In human clinical situations, allogeneic MSCs have a strong curative capacity in graft-versus-host-disease, for example. In addition, we routinely use human marrow-derived, culture expanded MSCs in a variety of animal models of disease as do others [11,[22][23][24]. The human cells in animal models are not immune privileged, but are rather immune-evasive (another attribute of the curtain which does not make the MSCs invisible to the immune system, but puts off the initial interrogation) [25].…”

“…The human cells in animal models are not immune privileged, but are rather immune-evasive (another attribute of the curtain which does not make the MSCs invisible to the immune system, but puts off the initial interrogation) [25]. I would assert that the use of human MSCs in animal models of disease is a more appropriate pre-clinical model than had we used syngeneic or animal matched MSCs [11,19,20,26]. I would further suggest that the release criteria for different commercial production runs of culture expanded human MSCs should be tested in appropriate rodent disease models as an in vivo assay.…”

Body Management: Mesenchymal Stem Cells Control the Internal Regenerator

“…The MSCs can then revert to their pericyte phenotype and attach to these new, fragile vessels to stabilize them. Indeed, it has been shown that MSC engraftment into injured marrow involves the MSCs taking up a perivascular location [45]. The final group includes molecules that function as mitogens for tissue-specific progenitors.…”