Kindlin-2 Modulates the Survival, Differentiation, and Migration of Induced Pluripotent Cell-Derived Mesenchymal Stromal Cells

Abstract

Kindlin-2 is a multidomain intracellular protein that can be recruited to β-integrin domains to activate signaling, initiate transcriptional programs, and bind to E-cadherin. To explore its involvement in cell fate decisions in mesenchymal cells, we studied the effects of Kindlin-2 modification (overexpression/knockdown) in induced pluripotent cell-derived mesenchymal stromal cells (iPSC-MSCs). Kindlin-2 overexpression resulted in increased proliferation and reduced apoptosis of iPSC-MSCs, as well as inhibition of their differentiation towards osteocytes, adipocytes, and chondrocytes. In contrast, siRNA-mediated Kindlin-2 knockdown induced increased apoptosis and increased differentiation response in iPSC-MSCs. The ability of iPSC-MSCs to adhere to VCAM-1/SDF-1α under shear stress and to migrate in a wound scratch assay was significantly increased after Kindlin-2 overexpression. In contrast, inhibition of mixed lymphocyte reaction (MLR) was generally independent of Kindlin-2 modulation in iPSC-MSCs, except for decreased production of interleukin-2 (IL-2) after Kindlin-2 overexpression in iPS-MSCs. Thus, Kindlin-2 upregulates survival, proliferation, stemness, and migration potential in iPSC-MSCs and may therefore be beneficial in optimizing performance of iPSC-MSC in therapies.

Kindlin-2 regulates hepatic stellate cells activation and liver fibrogenesis

“…Global deficiency of Kindlin-2 in mice caused early embryonic lethality, suggesting that Kindlin-2 plays a vital role in development 12 . Furthermore, recent reports have demonstrated that Kindlin-2 participates in numerous biological and pathological processes, such as cell apoptosis, differentiation, survival, and carcinogenesis 15 – 20 . Recently, Kindlin-2 was also reported to play an essential role in fibrotic disorders.…”

Kindlin-2 regulates the differentiation of 3T3-L1 preadipocytes: implications for wound healing

“…Kindlin-2, a component of cell-extracellular matrix adhesions, activates integrin by binding with the cytoskeletal protein, talin and regulates cell adhesion, migration, proliferation, and differentiation (21). Recently, evidence has emerged that kindlin-2 holds great potential in wound healing and cell differentiation (17)(18)(19). The present study identified kindlin-2 as a key determinant of the differentiation of 3T3-L1 preadipocytes in wound healing and delineated the underlying signaling mechanism.…”

“…Wu et al and Guo et al demonstrated that depletion of kindlin-2 in MSCs inhibits cartilage formation, damages bone development, induces adipogenesis, and inhibits osteogenesis through controlling Yes-associated protein 1 (YAP1) and Taffazzin (TAZ) which are key signaling intermediates that link adhesive and mechanical cues to MSC differentiation (17,19). In iPSC-MSCs, overexpression of kindlin-2 leads to increased proliferation and decreased apoptosis, and inhibits their differentiation into osteocytes, adipocytes, and chondrocytes (18). Noticeably, we observed that kindlin-2 has the opposite effect of inducing adipogenesis and osteogenesis in 3T3-L1 preadipocytes.…”

“…This suggests that kindlin-2 may have an important function in wound healing, but the specific mechanism is still unclear (16). In terms of regulating cell differentiation, kindlin-2 is essential for chondrogenesis and regulates the differentiation of pluripotent cell-derived mesenchymal stromal cells (iPSC-MSCs) and bone marrow mesenchymal stem cells (BM-MSCs) (17)(18)(19). However, whether or not kindlin-2 regulates preadipocyte differentiation, its potential role in wound healing, and the underlying mechanism remain undetermined.…”

Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine

“…Kindlin-2 knockdown increased apoptosis and differentiation response whereas kindlin-2 overexpression increased proliferation, decreased apoptosis, and slowed down trilineage differentiation. More significantly, kindlin-2 overexpression increased the migration of iPSC-MSCs in the wound-scratch assay[ 130 ]. In the future, substantial efforts are needed to explore MSC stemness/potency-related regulators or biomarkers for clinical application.…”