Bone marrow-derived mesenchymal stromal cell: what next?

Authors Borges FT, Convento MB, Schor N Received 11 June 2018 Accepted for publication 3 September 2018 Published 8 November 2018 Volume 2018:11 Pages 77—83 DOI https://doi.org/10.2147/SCCAA.S147804 Checked for plagiarism Yes Review by Single-blind Peer reviewers approved by Dr Amy Norman Peer reviewer comments 3 Editor who approved publication: Dr Bernard Binetruy Fernanda T Borges,1,2 Marcia Bastos Convento,1 Nestor Schor1,† 1Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, SP, Brazil; 2Interdisciplinary Postgraduate Program in Health Sciences, Universidade Cruzeiro do Sul, São Paulo, SP, Brazil †Professor Nestor Schor passed away on February 2, 2018 Abstract: Bone marrow mesenchymal stromal cell (MSC) is a potential alternative in regenerative medicine and has great potential in many pathologic conditions including kidney disease. Although most of the studies demonstrate MSC efficiency, the regenerative potential may not be efficient in all diseases and patients. Stem cell feasibility is modified by donor characteristics as gender, age, diet, and health status, producing both positive and negative results. The conditioning of MSC can potentiate its effects and modify its culture medium (CM). In current practices, the cell-free treatment is gaining notable attention, while MSC-conditioned CM is being applied and studied in many experimental diseases, including, but not limited to, certain kidney diseases. This may be the next step for clinical trials. Studies in stem cell CM have focused mainly on extracellular vesicles, nucleic acids (mRNA and microRNA), lipids, and proteins presented in this CM. They mediate regenerative effects of MSC in a harmonic manner. In this review, we will analyze the regenerative potential of MSC and its CM as well as discuss some effective techniques for modifying its fractions and improving its therapeutic potential. CM fractions may be modified by hypoxic conditions, inflammation, lipid exposition, and protein growth factors. Other possible mechanisms of action of stem cells are also suggested. In the future, the MSC paracrine effect may be modified to more closely meet each patient’s needs. Keywords: mesenchymal stromal cells, secretome, extracellular vesicles, microRNAs, lipids, growth factor Introduction Stem cell therapy is a potential alternative for many pathological conditions, including kidney diseases. Stem cell is characterized by maintaining unlimited self-renewing ability, remaining indefinitely undifferentiated, and possessing the capacity to differentiate and transform into cells with a specific phenotype.1 Stem cells differ according to their differentiation capabilities. Pluripotent stem cells, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), differentiate in almost all mammalian cell lineages. Multipotent or adult stem cells have limited differentiation capacities, are present in specific niches in mammalian organs, and are sources of cell renewal.2 In mammals, progenitor mesenchymal cells participate in the glomerular and tubule development, but in adult kidneys, progenitor population disappears. Nevertheless, some studies suggest the presence of these progenitor cells in adult kidneys3–5 and employ progenitor cells to treat experimental models of kidney diseases.6–8 The number of studies mentioning stem cells increases each year. A search on PubMed during the first semester of 2018 coupled with the term “stem cell” found almost 23,000 articles. One of the cells most frequently studied is the mesenchymal stem cell or mesenchymal stromal cell (MSC).9 Initially obtained from bone marrow (BM-MSC), MSCs are multipotent stem cells that present positive surface markers like CD90, CD105, and CD73 and negative surface markers such as CD45, CD34, CD14, CD79α, CD11b, CD19, or Human Leukocyte Antigen-DR isotype molecules.10 Additionally, they transformed into mesoderm-derived cell types including adipocytes, chondrocytes, and osteocytes.11 Nevertheless, similar cells were obtained from almost all adult tissues and organs when introduced in culture conditions including peripheral blood, liver, spleen, placenta, umbilical cord, and amniotic membrane.9 BM-MSC was the first stem cell well-characterized,12–14 and the MSC most often studied either in vitro or in vivo. Its protective and regenerative potential was demonstrated not only in experimental models of acute kidney injury induced by cisplatin,15 gentamicin,16 ischemia, and reperfusion17 but also in chronic kidney disease.18,19 One frequently investigated aspect of MSC is its mechanism of action. Initially, three hypotheses were suggested: first was the homing to the injury site and fusion with the resident cell, second was the transdifferentiation into the resident cell and repopulation of injured tissue, and third was the paracrine effect.20 Currently, the most widely accepted hypothesis is the paracrine effect, at least in regard to kidney diseases. To prove the final hypothesis, studies used the culture medium (CM) of stem cells to reproduce their regenerative effect on pathological conditions.21,22 The advantage of using the CM is the lower risk of immunogenicity or tumorigenicity. The ability to induce teratoma was notably demonstrated by the use of pluripotent stem cells including iPSCs23 and ESCs.24 Initially, it was reported that no tumor was detected after the transplant of human or animal MSCs,25 suggesting MSC was not tumorigenic. Nevertheless, other studies reported malignant lesions that have the capability of transforming into tumors even after the transplant of MSC has occurred.26,27 Cell-free therapy reinforces the concept that the MSC-CM is a safe option for the use of the cell. MSC, in naive conditions, expresses intermediate major histocompatibility complex class I molecules as opposed to class II molecules. These molecules are not recognized by alloreactive T-cells, showing low level of immunogenicity. Additionally, BM-MSC have potent immunosuppressive effects, which corroborate the low immunogenicity.28 Nevertheless, it is noteworthy to emphasize that most studies regarding BM-MSC analyzed their protective/regenerative effects only for a few days or weeks, and consequently suggest that stem cells were washed out from the site after 24 hours or if they were trapped in the lungs.29 Manuscripts focusing on the immunogenicity or tumorigenicity of BM-MSC for long periods after transplant occurred were not conducted extensively and are still necessary in current practice. The MSC-CM and its modification The CM of MSC or its secretome is composed mainly of lipids, proteins, and nucleic acid-enriched extracellular vesicles (EVs). Each fraction of CM has been analyzed by its regenerative and/or protective properties, but the secretome most likely works in a harmonic way and not in an independent (...truncated)