Bone marrow vs Wharton’s jelly mesenchymal stem cells in experimental sepsis: a comparative study

Background

The use of mesenchymal stem cells (MSCs) is being extensively studied in clinical trials in the setting of various diseases including diabetes, stroke, and progressive multiple sclerosis. The unique immunomodulatory properties of MSCs also point them as a possible therapeutic tool during sepsis and septic shock, a devastating syndrome associated with 30–35% mortality. However, MSCs are not equal regarding their activity, depending on their tissue origin. Here, we aimed at comparing the in vivo properties of MSCs according to their tissue source (bone marrow (BM) versus Wharton’s jelly (WJ)) in a murine cecal ligation and puncture (CLP) model of sepsis that mimics a human peritonitis. We hypothesized that MSC properties may vary depending on their tissue source in the setting of sepsis.

Methods

CLP, adult, male, C57BL/6 mice were randomized in 3 groups receiving respectively 0.25 × 106 BM-MSCs, 0.25 × 106 WJ-MSCs, or 150 μL phosphate-buffered saline (PBS) intravenously 24 h after the CLP procedure.

Results

We observed that both types of MSCs regulated leukocyte trafficking and reduced organ dysfunction, while only WJ-MSCs were able to improve bacterial clearance and survival.

Conclusion

This study highlights the importance to determine the most appropriate source of MSCs for a given therapeutic indication and suggests a better profile for WJ-MSCs during sepsis.

Mesenchymal stem cell (MSC) administration is being extensively studied in clinical trials in the setting of many different disorders such as graft versus host disease, cardiomyopathy, diabetes, stroke, bronchopulmonary dysplasia, progressive multiple sclerosis, or osteoarthritis. Indeed, MSCs are an attractive therapeutic candidate for several reasons: these cells display immunomodulatory, anti-inflammatory, antibacterial, and differentiation properties [1]. Their isolation and expansion are both easy and fast as compare to other stem cells like embryonic stem cells. They are devoid of MHC class II antigens and express only low levels of MHC class I antigens, allowing their use in an allogeneic setting due to their low immunogenicity [2]. Finally, several clinical trials reported no adverse events after MSC infusion, describing those cells as safe for clinical use [3].

Since their discovery in the bone marrow (BM) by Friedenstein’s team in 1976, MSCs have been found in the skeletal muscle, adipose tissue [4], dental pulp, trabecular bone synovial membrane, lungs [5], heart [6], synovial membrane, trabecular bone, periosteum [7, 8], and menstrual blood [9], as well as in different birth tissues, including the amniotic fluid and membrane [10], placenta [11], umbilical cord blood [12], and Wharton’s jelly (WJ) [13].

The International Society for Cellular Therapies defined MSCs as (i) CD34neg CD45neg HLADRneg CD90+ CD73+ CD105+ cells with (ii) plastic adherence (iii) and ability to differentiate into osteocytes, adipocytes, and chondrocytes. However, despite this consensual definition, MSCs remain a very heterogeneous cell population and large variations in their properties, partly related to their tissue source, have been described [14]. For example, Alcayaga et al. demonstrated a superior frequency of menstrual stem cell fibroblast colony-forming units as compared to bone marrow stem cells (BM-MSCs) [15]. Paneppucci et al. described better osteogenic differentiation when MSCs were derived from BM as compared to WJ [16]. Li et al. found that MSCs from birth tissues have stronger immunomodulatory properties than BM-derived cells [17]. Accordingly, it is essential to determine the most suitable source of MSCs to get the best-expected effect depending on the therapeutic indication considered.

Sepsis, defined as life-threatening organ dysfunction caused by a deregulated host response to infection, is a leading cause of admission to intensive care units and is associated with high mortality rates [18, 19]. Unfortunately, due to its complex physiopathology, there is still no specific treatment for this syndrome. Mei et al. [20] were the first to suggest that MSCs improve survival and decrease organ failure in a mouse model of endotoxemia, and subsequent studies showed that MSCs can increase bacterial clearance [21], modulate cytokine production [22,23,24,25], and improve renal, pulmonary, liver, cardiac, and muscular functions [21, 26,27,28,29]. Although promising, these studies used MSCs derived from adult tissues (BM and adipose tissue) exhibiting many drawbacks with regard to their potential for clinical applications: the number of adult MSC donors is limited, and adult MSCs remain difficult to produce. By contrast, fetal tissues, and particularly the umbilical cord, are much easier to obtain and MSCs are present in large numbers in these tissues and can be expanded [30].

Therefore, in this study, we compared the in vivo properties of MSCs according to their tissue source: BM versus WJ, which is an attractive source due to its abundance, during a cecal ligation and puncture model of sepsis that mimics a human peritonitis with immune deregulation, organ injury bacterial invasion [31]. We hypothesized that MSC properties may vary depending on their tissue source in the setting of sepsis.

MSC preparation