Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

Abstract

Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UCMSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSCs, contrary to BM-MSCs, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC-conditioned medium presented a distinct and stronger proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, the new bone was deposited through the activity of stimulated host cells, highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms.

Osteogenic potential of stem cells‐seeded bioactive nanocomposite scaffolds: A comparative study between human mesenchymal stem cells derived from bone, umbilical cord Wharton's jelly, and adipose tissue

“…In our study, newly formed vessels were evidently observed in the defects filled with the UC‐MSCs/scaffolds. These findings are in agreement with prior research in which MSCs derived from human umbilical cord significantly increased ingrowth of blood vessels in vivo compared to MSCs derived from bone marrow . Regeneration of new vessels in damaged sites is always considered as a very important issue in tissue regeneration, because new vessels are responsible for the transportation of nutrients and waste materials .…”

“…There was no woven bone tissue in the defects filled with the blank scaffold. These data are consistence with previous studies showing higher osteogenic differentiation potential of MSCs derived from bone marrow compared to other MSCs . Moreover, previous studies conducted on animals showed that the implantation of BM‐MSCs together with bioceramic‐based biomaterials lead to better results .…”

“…The MSCs were isolated using standard protocols, from bone marrow, umbilical cord Wharton's jelly, and adipose tissue. It has been showed that under appropriate conditions these cells can potentially promote the behavior of osteoblast cells in vitro . All the isolated MSCs were cultured to scale up for in vitro and in vivo applications.…”

Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid in vivo

“…Most importantly, the authors used 'MSCs' from the umbilical cord (UC), which are very different from the fibroblasts derived from CB that we used in this study (Reinisch et al, 2015). In particular, UC cells are not able to form bone in vivo, even when transplanted with an osteoconductive carrier (Kaltz et al, 2008;Todeschi et al, 2015). Moreover, significant differences have been found in the global gene expression profile of UC-derived cells and CB-BFs isolated from the same donor and cultured under the same culture conditions (Secco et al, 2009).…”

Fabrication of carbonate apatite honeycomb and its tissue response

“…An interconnected porous structure is attractive for bone substitutes because bone tissue and cells can penetrate the bone substitute . Furthermore, microporous structure should play an important role in cell growth and differentiation, similar to the niche environment or microenvironment produced by the extracellular matrix . Among many porous structures available, the honeycomb (HC) structure is unique due to its fully interconnected and oriented pores having the same pore size, and shows high mechanical strength in the direction of the pores …”