Bone Marrow-Derived Cells Contribute to Epithelial Engraftment during Wound Healing

Abstract

Recent findings suggest that bone marrow-derived cells (BMDC) may contribute to tissue maintenance throughout the body. However, it is not yet known whether marrow-derived epithelial cells are capable of undergoing proliferation. Our laboratory has shown that BMDC engraft as keratinocytes in the skin at low levels (< 1%) in the absence of injury. Here we show that skin damage affects the degree of engraftment of BMDC as keratinocytes and that the keratinocytes are actively cycling. Female mice reconstituted with sex-mismatched BM were wounded by punch biopsy and incision. At the wound site, engraftment of BMDC as epidermal cells increased within 1 day, and continued to increase to approximately 4% by 3 weeks after injury. Using a Cre-lox system, fusion of BMDC with epithelial cells was ruled out. BMDC-derived epithelial cells at the wound edges expressed Ki67, a marker for actively cycling cells, and this proliferation correlated with an increase in the number of donor-derived cells within the wound. Donorderived cytokeratin 5-expressing cells were rare, suggesting that BMDC do not engraft as epidermal stem cells, and the level of engraftment peaked and then decreased over time, further suggesting that BMDC may assist in early wound healing by engrafting as transit-amplifying cells, which then differentiate into keratinocytes. We have shown that, in the absence of injury, bone marrow-derived cells (BMDC) engraft at low levels as epithelial cells in the liver, lung, GI tract, and skin. It is not yet clear whether this phenomenon is due to transdifferentiation of a hematopoietic stem cell, or whether the marrow contains pluripotent pre-hematopoietic cells thathave not yet initiated a gene expression pattern that commits them to either a hematopoietic or an epithelial fate (reviewed in 1 ). According to recent studies, BMDC show an increased contribution to tissues under pathological conditions. Following acute myocardial infarction, BMDC engraft as multiple cell types that promote survival/regeneration of heart tissue.2,3 A more pronounced effect is seen in a mouse model of tyrosinemia, where fusion of BMDC with diseased cells results in the formation of functional hepatocytes and restores liver function. 4 These findings led us to investigate whether cutaneous injury leads to increased engraftment of BMDC as epidermal cells.To allow for tracking of the BMDC, we reconstituted lethally irradiated mice with sex-mismatched BM. Following engraftment, we wounded the skin with full-thickness punch biopsies and incisional wounds, each of which heals by secondary intention. Analysis of the healing skin at different times showed that engraftment of BMDC as epidermal cells in the wounded area was significantly greater than in unwounded skin over the same time interval. The marrow-derived epithelial cells just beyond the wound edges were undergoing proliferation. Fusion was ruled out using the loxP-Cre system. Based on the pattern of engraftment over time, a conceptual model of this engraftment is proposed. Materials and Met...

Circulating Progenitor Epithelial Cells Traffic via CXCR4/CXCL12 in Response to Airway Injury

“…2B, i, Table I, and data not shown). Other authors have also shown that not all male cells are positive for the Y chromosome by FISH, which may reflect the plane of sectioning of individual nuclei (17,18). Control female tracheal sections from female mice did not demonstrate any hybridization with the Y-labeled probe (Fig.…”

Plasminogen Activator Inhibitor-1 Controls Bone Marrow-Derived Cells Therapeutic Effect Through MMP9 Signaling: Role in Physiological and Pathological Wound Healing

“…Since wound closure involves mobilization and recruitment of BMMNC [13], we analyzed the role of PAI-1 and MMP9 in this process. When cultured in conditioned media from endothelial cells, PAI-1À/À BMMNC released high levels of MMP9 compared to WT BMMNC (Fig.…”

“…Bone morrow-derived cells contribute to epithelial engraftment during wound healing [13]. These findings let us to investigate whether PAI-1 deficiency through MMP9 promoted wound healing process.…”

PDGFRα-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia

“…BM can also generate epithelial cells, i.e., keratinocytes, in the epithelia, although the precise derivations and mechanisms to raise BM-derived keratinocytes are not fully known (3,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Human/mouse studies involving transplantation of sex-mismatched or genetically tagged BM cells have shown that keratin-positive bone marrow-derived cells can be found in skin epidermis, hair follicles, and sebaceous glands (6,8,9,11,12,14,16), sites that harbor skin stem cell niches (17). Moreover, in humans who have undergone BM transplantation (BMT), donor cells that have differentiated into keratinocytes can be detected in the epidermis for at least 3 y (8).…”