Stimulation of Skin and Wound Fibroblast Migration by Mesenchymal Stem Cells Derived from Normal Donors and Chronic Wound Patients

Abstract

Chronic wounds continue to be a major cause of morbidity for patients and an economic burden on the health care system. Novel therapeutic approaches to improved wound healing will need, however, to address cellular changes induced by a number of systemic comorbidities seen in chronic wound patients, such as diabetes, chronic renal failure, and arterial or venous insufficiency. These effects likely include impaired inflammatory cell migration, reduced growth factor production, and poor tissue remodeling. The multifunctional properties of bone marrow-derived mesenchymal stem cells (MSCs), including their ability to differentiate into various cell types and capacity to secrete factors important in accelerating healing of cutaneous wounds, have made MSCs a promising agent for tissue repair and regeneration. In this study we have used an in vitro scratch assay procedure incorporating labeled MSCs and fibroblasts derived from normal donors and chronic wound patients in order to characterize the induction of mobilization when these cells are mixed. A modified Boyden chamber assay was also used to examine the effect of soluble factors on fibroblast migration. These studies suggest that MSCs play a role in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner. Deficiencies were noted, however, in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These findings provide a foundation to develop therapies targeted specifically to the use of bone marrow-derived MSCs in wound healing and may provide insight into why some wounds do not heal.

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

“…Experiments utilizing MSC-conditioned media have demonstrated the importance of the paracrine mechanism of BM-MSC-induced wound healing [49][50][51][52]. More recent work in our laboratory has demonstrated that MSCs could enhance fibroblast migration without cell contact in a dosedependent manner [19].…”

“…Bone marrow-derived MSCs have been shown to be efficacious in the treatment of wounds, including chronic wounds [14,18,19]. Previous work in our laboratory has demonstrated that bone marrow-derived cells play an important role in cutaneous wound healing and that direct application of bone marrow-derived cells to patients with chronic nonhealing wounds leads to wound closure and dermal rebuilding [43][44][45][46][47].…”

“…Three different donors were used for these experiments. MSCs were isolated by the plastic adherence method as described in a previous study and found to be positive for CD105, CD90, CD73, HLA-Class-1, negative for CD45, and able to differentiate into osteogenic, chondrogenic and adipogenic lineages [19]. Stocks of low passage cells (passage < 5) were also cryopreserved until use.…”

“…Instead it is believed that MSCs exert their therapeutic effects by secreting soluble or ''paracrine'' factors that augment endogenous repair and regenerative mechanisms [15][16][17][18]. Also, work in our laboratory has found that MSCs can enhance fibroblast migration, an integral component of the wound healing process, without direct contact, suggesting the importance of paracrine signaling between these cells [19]. However, the exact molecular mechanisms of this correction are not clear.…”

The role of the microenvironment on the fate of adult stem cells

“…In chronic wound patients, such as patients with diabetes, chronic renal failure, and arterial or venous insufficiency, these effects likely include impaired inflammatory cell migration, reduced growth factor production, and poor tissue remodeling. Rodriguez-Menocal et al [58] studied fibroblasts derived from normal donors and chronic wound patients that were co-cultured after an in vitro scratch assay. They found that the migration ability was significantly reduced in the fibroblast treatment of BM-MSCs from chronic wound patients compared to MSCs from normal donors.…”